@article {233, title = {Co-Expression Network Analysis of Fbxw7-Associated LncRNAs Reveals Their Functions in Radiation-Induced Thymic Lymphoma.}, journal = {Insights Cancer Res}, volume = {1}, year = {2016}, month = {2016}, pages = {1-5}, abstract = {

FBXW7, an E3-ubiquitin protein ligase in SCFs (SKP1-cullin-F-box) complex, is a major human tumor suppressor gene, and understanding mechanisms by which FBXW7 contributes to tumorigenesis is critical for the treatment of human cancers with FBXW7 deficiency. Long non-coding RNAs (lncRNAs) have emerged as key regulators of various biological processes. Here we have identified a set of lncRNAs that are associated with Fbxw7 deficiency. The correlation network and functional annotation analysis revealed that Fbxw7-associated lncRNAs regulate genes involved in cell cycle, DNA repair, metabolic process, and cell communication and adhesion. The number of coding genes that correlated with individual lncRNAs varied largely. A lncRNA on chromosome 15 (A_30_P01032978), which was upregulated in tumors from Fbxw7 deficient mice was positively correlated with 15 coding genes. High expression of this 15-gene signature was associated with poor prognosis in two independent human breast cancer studies. Our results open possible new avenues to understand mechanisms by which Fbxw7 deficiency increases tumor susceptibility via the alteration of lncRNAs.

}, author = {A Snijders and Jiang-Hua Mao} } @article {238, title = {Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer.}, journal = {Breast Cancer Res}, volume = {18}, year = {2016}, month = {2016}, pages = {70}, abstract = {

BACKGROUND: High mitotic activity is associated with the genesis and progression of many cancers. Small molecule inhibitors of mitotic apparatus proteins are now being developed and evaluated clinically as anticancer agents. With clinical trials of several of these experimental compounds underway, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that carry molecular aberrations that confer high mitotic activity, and to develop molecular markers that distinguish which tumors will be most responsive to mitotic apparatus inhibitors.

METHODS: We identified a coordinately regulated mitotic apparatus network by analyzing gene expression profiles for 53 malignant and non-malignant human breast cancer cell lines and two separate primary breast tumor datasets. We defined the mitotic network activity index (MNAI) as the sum of the transcriptional levels of the 54 coordinately regulated mitotic apparatus genes. The effect of those genes on cell growth was evaluated by small interfering RNA (siRNA).

RESULTS: High MNAI was enriched in basal-like breast tumors and was associated with reduced survival duration and preferential sensitivity to inhibitors of the mitotic apparatus proteins, polo-like kinase, centromere associated protein E and aurora kinase designated GSK462364, GSK923295 and GSK1070916, respectively. Co-amplification of regions of chromosomes 8q24, 10p15-p12, 12p13, and 17q24-q25 was associated with the transcriptional upregulation of this network of 54 mitotic apparatus genes, and we identify transcription factors that localize to these regions and putatively regulate mitotic activity. Knockdown of the mitotic network by siRNA identified 22 genes that might be considered as additional therapeutic targets for this clinically relevant patient subgroup.

CONCLUSIONS: We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.

}, issn = {1465-542X}, doi = {10.1186/s13058-016-0728-y}, author = {Hu, Zhi and Jiang-Hua Mao and Curtis, Christina and Huang, Ge and Gu, Shenda and Heiser, Laura and Lenburg, Marc E and Korkola, James E and Bayani, Nora and Samarajiwa, Shamith and Seoane, Jose A and A Dane, Mark and Esch, Amanda and Feiler, Heidi S and Wang, Nicholas J and Hardwicke, Mary Ann and Laquerre, Sylvie and Jackson, Jeff and W Wood, Kenneth and Weber, Barbara and Spellman, Paul T and Aparicio, Samuel and Wooster, Richard and Caldas, Carlos and Gray, Joe W} } @article {232, title = {HZE Radiation Non-Targeted Effects on the Microenvironment That Mediate Mammary Carcinogenesis.}, journal = {Front Oncol}, volume = {6}, year = {2016}, month = {2016}, pages = {57}, abstract = {

Clear mechanistic understanding of the biological processes elicited by radiation that increase cancer risk can be used to inform prediction of health consequences of medical uses, such as radiotherapy, or occupational exposures, such as those of astronauts during deep space travel. Here, we review the current concepts of carcinogenesis as a multicellular process during which transformed cells escape normal tissue controls, including the immune system, and establish a tumor microenvironment. We discuss the contribution of two broad classes of radiation effects that may increase cancer: radiation targeted effects that occur as a result of direct energy deposition, e.g., DNA damage, and non-targeted effects (NTE) that result from changes in cell signaling, e.g., genomic instability. It is unknown whether the potentially greater carcinogenic effect of high Z and energy (HZE) particle radiation is a function of the relative contribution or extent of NTE or due to unique NTE. We addressed this problem using a radiation/genetic mammary chimera mouse model of breast cancer. Our experiments suggest that NTE promote more aggressive cancers, as evidenced by increased growth rate, transcriptomic signatures, and metastasis, and that HZE particle NTE are more effective than reference γ-radiation. Emerging evidence suggest that HZE irradiation dampens antitumor immunity. These studies raise concern that HZE radiation exposure not only increases the likelihood of developing cancer but also could promote progression to more aggressive cancer with a greater risk of mortality.

}, issn = {2234-943X}, doi = {10.3389/fonc.2016.00057}, author = {Barcellos-Hoff, Mary Helen and Jiang-Hua Mao} } @article {235, title = {Knockdown of cullin 4A inhibits growth and increases chemosensitivity in lung cancer cells.}, journal = {J Cell Mol Med}, volume = {20}, year = {2016}, month = {2016 Jul}, pages = {1295-306}, abstract = {

Cullin 4A (Cul4A) has been observed to be overexpressed in various cancers. In this study, the role of Cul4A in the growth and chemosensitivity in lung cancer cells were studied. We showed that Cul4A is overexpressed in lung cancer cells and tissues. Knockdown of the Cul4A expression by shRNA in lung cancer cells resulted in decreased cellular proliferation and growth in lung cancer cells. Increased sensitivity to gemcitabine, a chemotherapy drug, was also noted in those Cul4A knockdown lung cancer cells. Moreover, increased expression of p21, transforming growth factor (TGF)-β inducible early gene-1 (TIEG1) and TGF beta-induced (TGFBI) was observed in lung cancer cells after Cul4A knockdown, which may be partially related to increased chemosensitivity to gemcitabine. G0/G1 cell cycle arrest was also noted after Cul4A knockdown. Notably, decreased tumour growth and increased chemosensitivity to gemcitabine were also noted after Cul4A knockdown in lung cancer xenograft nude mice models. In summary, our study showed that targeting Cul4A with RNAi or other techniques may provide a possible insight to the development of lung cancer therapy in the future.

}, issn = {1582-4934}, doi = {10.1111/jcmm.12811}, author = {Hung, Ming-Szu and Chen, I-Chuan and You, Liang and Jablons, David M and Li, Ya-Chin and Jiang-Hua Mao and Xu, Zhidong and Lung, Jr-Hau and Yang, Cheng-Ta and Liu, Shih-Tung} } @article {237, title = {Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes.}, journal = {Bioessays}, volume = {38}, year = {2016}, month = {2016 Jul}, pages = {664-73}, abstract = {

Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as "missing heritability." Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases.

}, issn = {1521-1878}, doi = {10.1002/bies.201600084}, author = {Blanco-G{\'o}mez, Adri{\'a}n and Castillo-Lluva, Sonia and Del Mar S{\'a}ez-Freire, Mar{\'\i}a and Hontecillas-Prieto, Lourdes and Jiang-Hua Mao and Castellanos-Mart{\'\i}n, Andr{\'e}s and Perez-Losada, Jesus} } @article {239, title = {A novel gene expression-based prognostic scoring system to predict survival in gastric cancer.}, journal = {Oncotarget}, year = {2016}, month = {2016 Jul 11}, abstract = {

Analysis of gene expression patterns in gastric cancer (GC) can help to identify a comprehensive panel of gene biomarkers for predicting clinical outcomes and to discover potential new therapeutic targets. Here, a multi-step bioinformatics analytic approach was developed to establish a novel prognostic scoring system for GC. We first identified 276 genes that were robustly differentially expressed between normal and GC tissues, of which, 249 were found to be significantly associated with overall survival (OS) by univariate Cox regression analysis. The biological functions of 249 genes are related to cell cycle, RNA/ncRNA process, acetylation and extracellular matrix organization. A network was generated for view of the gene expression architecture of 249 genes in 265 GCs. Finally, we applied a canonical discriminant analysis approach to identify a 53-gene signature and a prognostic scoring system was established based on a canonical discriminant function of 53 genes. The prognostic scores strongly predicted patients with GC to have either a poor or good OS. Our study raises the prospect that the practicality of GC patient prognosis can be assessed by this prognostic scoring system.

}, issn = {1949-2553}, doi = {10.18632/oncotarget.10533}, author = {Wang, Pin and Wang, Yunshan and Hang, Bo and Zou, Xiaoping and Jiang-Hua Mao} } @article {102, title = {Phenotypic Characterization of Breast Invasive Carcinoma via Transferable Tissue Morphometric Patterns learned from Glioblastoma Multiforme.}, journal = {Proc IEEE Int Symp Biomed Imaging}, volume = {2016}, year = {2016}, month = {2016 Apr}, pages = {1025-1028}, abstract = {

Quantitative analysis of whole slide images (WSIs) in a large cohort may provide predictive models of clinical outcome. However, the performance of the existing techniques is hindered as a result of large technical variations (e.g., fixation, staining) and biological heterogeneities (e.g., cell type, cell state) that are always present in a large cohort. Although unsupervised feature learning provides a promising way in learning pertinent features without human intervention, its capability can be greatly limited due to the lack of well-curated examples. In this paper, we explored the transferability of knowledge acquired from a well-curated Glioblastoma Multiforme (GBM) dataset through its application to the representation and characterization of tissue histology from the Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (BRCA) cohort. Our experimental results reveals two major phenotypic subtypes with statistically significantly different survival curves. Further differential expression analysis of these two subtypes indicates enrichment of genes regulated by NF-kB in response to TNF and genes up-regulated in response to IFNG.

}, issn = {1945-7928}, doi = {10.1109/ISBI.2016.7493440}, author = {Han, Ju and Fontenay, Gerald V and Wang, Yunfu and Jiang-Hua Mao and Hang Chang} } @article {234, title = {Prognostic significance of FAM83D gene expression across human cancer types.}, journal = {Oncotarget}, volume = {7}, year = {2016}, month = {2016 Jan 19}, pages = {3332-40}, abstract = {

The family with sequence similarity 83, member D (FAM83D) gene has been proposed as a new prognostic marker for breast cancer. Here we further evaluate the prognostic significance of FAM83D expression in different breast cancer subtypes using a meta-analysis. Patients with higher FAM83D mRNA levels have significantly decreased overall and metastatic relapse-free survival, particularly in the group of patients with ER-positive, or luminal subtype tumors. We also assessed FAM83D alterations and its prognostic significance across 22 human cancer types using The Cancer Genome Atlas (TCGA). FAM83D is frequently gained in the majority of human cancer types, resulting in the elevated expression of FAM83D. Higher levels of FAM83D mRNA expression are significantly associated with decreased overall survival in several cancer types. Finally, we demonstrate that TP53 mutation in human cancers is coupled to a significant increase in the expression of FAM83D, and that a higher level of FAM83D expression is positively correlated with an increase in genome instability in many cancer types. These results identify FAM83D as a potential novel oncogene across multiple human cancer types.

}, issn = {1949-2553}, doi = {10.18632/oncotarget.6620}, author = {Walian, Peter J and Hang, Bo and Jiang-Hua Mao} } @article {236, title = {Tobacco toxins deposited on surfaces (third hand smoke) impair wound healing.}, journal = {Clin Sci (Lond)}, volume = {130}, year = {2016}, month = {2016 Jul 1}, pages = {1269-84}, abstract = {

Third hand smoke (THS) is the accumulation of second hand smoke (SHS) toxins on surfaces in homes, cars, clothing and hair of smokers. It is known that 88M US nonsmokers >=3~years old living in homes of smokers are exposed to THS toxicants and show blood cotinine levels of >=0.05~ng/ml, indicating that the toxins are circulating in their circulatory systems. The goal of the present study is to investigate the mechanisms by which THS causes impaired wound healing. We show that mice living under conditions that mimic THS exposure in humans display delayed wound closure, impaired collagen deposition, altered inflammatory response, decreased angiogenesis, microvessels with fibrin cuffs and a highly proteolytic wound environment. Moreover, THS-exposed mouse wounds have high levels of oxidative stress and significantly lower levels of antioxidant activity leading to molecular damage, including protein nitration, lipid peroxidation and DNA damage that contribute to tissue dysfunction. Furthermore, we show that elastase is elevated, suggesting that elastin is degraded and the plasticity of the wound tissue is decreased. Taken together, our results lead us to conclude that THS toxicants delay and impair wound healing by disrupting the sequential processes that lead to normal healing. In addition, the lack of elastin results in loss of wound plasticity, which may be responsible for reopening of wounds.

}, issn = {1470-8736}, doi = {10.1042/CS20160236}, author = {Dhall, Sandeep and Alamat, Raquelle and Castro, Anthony and Sarker, Altaf H and Jiang-Hua Mao and Chan, Alex and Hang, Bo and Martins-Green, Manuela} } @article {240, title = {The Trp53 delta proline (Trp53ΔP) mouse exhibits increased genome instability and susceptibility to radiation-induced, but not spontaneous, tumor development.}, journal = {Mol Carcinog}, volume = {55}, year = {2016}, month = {2016 Sep}, pages = {1387-96}, abstract = {

The tumor suppressor TP53 can initiate a plethora of anti-proliferative effects to maintain genomic integrity under conditions of genotoxic stress. The N-terminal proline-rich domain (PRD) of TP53 is important in the regulation of TP53 activity and stability. A common polymorphism at codon 72 in this region has been associated with altered cancer risk in humans. The Trp53ΔP mouse, which carries a germline homozygous deletion of a region of the PRD, does not develop spontaneous tumors in a mixed 129/Sv and C57BL/6 genetic background, but is highly susceptible to a broad range of tumor types following total body exposure to 4 Gy gamma (γ) radiation. This contrasts with the tumor spectrum in Trp53 null (-/-) mice, which mainly develop thymic lymphomas and osteosarcomas. Analysis of genomic instability in tissues and cells from Trp53ΔP mice demonstrated elevated basal levels of aneuploidy, but this is not sufficient to drive spontaneous tumorigenesis, which requires an additional DNA damage stimulus. Levels of genomic instability did not increase significantly in Trp53ΔP mice following irradiation exposure, suggesting that other radiation effects including tissue inflammation, altered metabolism or autophagy, may play an important role. The Trp53ΔP mouse is a novel model to dissect the mechanisms of tumor development induced by radiation exposure. {\textcopyright} 2015 Wiley Periodicals, Inc.

}, issn = {1098-2744}, doi = {10.1002/mc.22377}, author = {Adams, Cassandra J and Yu, Jennifer S and Jiang-Hua Mao and Jen, Kuang-Yu and Costes, Sylvain V and Wade, Mark and Shoemake, Jocelyn and Aina, Olulanu H and Del Rosario, Reyno and Menchavez, Phuong Thuy and Cardiff, Robert D and Wahl, Geoffrey M and Balmain, Allan} } @article {223, title = {Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene.}, journal = {Thorac Cancer}, volume = {6}, year = {2015}, month = {2015 Jul}, pages = {480-7}, abstract = {

BACKGROUND: Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully recapitulate the complexities of human lung cancer. The pathogenesis of lung cancer remains highly elusive because of its aggressive biologic nature and considerable heterogeneity, compared to other cancers. The association of Cul4A amplification with aggressive tumor growth and poor prognosis has been suggested. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied.

METHODS: Viral delivery approaches have been used extensively to model cancer in mouse models. In our experiments, we used Cre-recombinase induced overexpression of the Cul4A gene in transgenic mice to study the role of Cul4A on lung tumor initiation and progression and have developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A.

RESULTS: Here we show that the use of a recombinant adenovirus expressing Cre-recombinase ("AdenoCre") to induce Cul4A overexpression in the lungs of mice allows controls of the timing and multiplicity of tumor initiation. Following our mouse models, we are able to study the potential role of Cul4A in the development and progression in pulmonary adenocarcinoma as well.

CONCLUSION: Our findings indicate that Cul4A is oncogenic in vivo, and this mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.

}, issn = {1759-7706}, doi = {10.1111/1759-7714.12257}, author = {Wang, Yang and Xu, Zhidong and Jiang-Hua Mao and Hung, Ming-Szu and Hsieh, David and Au, Alfred and Jablons, David M and You, Liang} } @article {227, title = {Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma.}, journal = {J Cell Mol Med}, volume = {19}, year = {2015}, month = {2015 Oct}, pages = {2385-96}, abstract = {

Malignant pleural mesothelioma (mesothelioma) is a highly aggressive cancer without an effective treatment. Cul4A, a scaffold protein that recruits substrates for degradation, is amplified in several human cancers, including mesothelioma. We have recently shown that Cul4A plays an oncogenic role in vitro and in a mouse model. In this study, we analysed clinical mesothelioma tumours and found moderate to strong expression of Cul4A in 70.9\% (51/72) of these tumours, as shown by immunohistochemistry. In 72.2\% mesothelioma tumours with increased Cul4A copy number identified by fluorescence in situ hybridization analysis, Cul4A protein expression was moderate to strong. Similarly, Cul4A was overexpressed and Cul4A copy number was increased in human mesothelioma cell lines. Because Gli1 is highly expressed in human mesothelioma cells, we compared Cul4A and Gli1 expression in mesothelioma tumours and found their expression associated (P < 0.05, chi-square). In mesothelioma cell lines, inhibiting Cul4A by siRNA decreased Gli1 expression, suggesting that Gli1 expression is, at least in part, regulated by Cul4A in mesothelioma cells. Our results suggest a linkage between Cul4A and Gli1 expression in human mesothelioma.

}, keywords = {Case-Control Studies, Cell Line, Tumor, Chi-Square Distribution, Cullin Proteins, Gene Dosage, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lung Neoplasms, Mesothelioma, Pleural Neoplasms, Real-Time Polymerase Chain Reaction, RNA, Messenger, Transcription Factors}, issn = {1582-4934}, doi = {10.1111/jcmm.12620}, author = {Yang, Yi-Lin and Ni, Jian and Hsu, Ping-Chih and Jiang-Hua Mao and Hsieh, David and Xu, Angela and Chan, Geraldine and Au, Alfred and Xu, Zhidong and Jablons, David M and You, Liang} } @article {226, title = {Elevated expression of UBE2T exhibits oncogenic properties in human prostate cancer.}, journal = {Oncotarget}, volume = {6}, year = {2015}, month = {2015 Sep 22}, pages = {25226-39}, abstract = {

Increased expression of ubiquitin-conjugating enzyme E2T (UBE2T) is reported in human prostate cancer. However, whether UBE2T plays any functional role in prostate cancer development remains unknown. We here report the first functional characterization of UBE2T in prostate carcinogenesis. Prostate cancer tissue array analysis confirmed upregulation of UBE2T in prostate cancer, especially these with distant metastasis. Moreover, higher level of UBE2T expression is associated with poorer prognosis of prostate cancer patients. Ectopic expression of UBE2T significantly promotes prostate cancer cell proliferation, motility and invasion, while UBE2T depletion by shRNA significantly inhibits these abilities of prostate cancer cells. Xenograft mouse model studies showed that overexpression of UBE2T promotes whereas UBE2T depletion inhibits tumor formation and metastasis significantly. Collectively, we identify critical roles of UBE2T in prostate cancer development and progression. These findings may serve as a framework for future investigations designed to more comprehensive determination of UBE2T as a potential therapeutic target.

}, keywords = {Cell Line, Tumor, Cell Movement, Cell Proliferation, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Heterografts, Humans, Kaplan-Meier Estimate, Male, Neoplasm Invasiveness, Neoplasm Transplantation, Prognosis, Prostatic Neoplasms, RNA Interference, Signal Transduction, Time Factors, Transfection, Ubiquitin-Conjugating Enzymes, Up-Regulation}, issn = {1949-2553}, doi = {10.18632/oncotarget.4712}, author = {Wen, Mingxin and Kwon, Yongwon and Wang, Yongsheng and Jiang-Hua Mao and Wei, Guangwei} } @article {231, title = {Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic lymphomas.}, journal = {Oncotarget}, volume = {6}, year = {2015}, month = {2015 Dec 29}, pages = {44794-805}, abstract = {

The tumor suppressor gene FBXW7 is deleted and mutated in many different types of human cancers. FBXW7 primarily exerts its tumor suppressor activity by ubiquitinating different oncoproteins including mTOR. Here we used gene transcript profiling to gain a deeper understanding of the role of FBXW7 in tumor development and to determine the influence of mTOR inhibition by rapamycin on tumor transcriptome and biological functions. In comparison to tumors from p53 single heterozygous (p53+/-) mice, we find that radiation-induced thymic lymphomas from Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice show significant deregulation of cholesterol metabolic processes independent of rapamycin treatment, while cell cycle related genes were upregulated in tumors from placebo treated Fbxw7+/-p53+/- mice, but not in tumors from rapamycin treated Fbxw7+/-p53+/- mice. On the other hand, tumors from rapamycin treated Fbxw7+/-p53+/- mice were enriched for genes involved in the integrated stress response, an adaptive mechanism to survive in stressful environments. Finally, we demonstrated that the Fbxw7 gene signatures identified in mouse tumors significantly overlap with FBXW7 co-expressed genes in human cancers. Importantly these common FBXW7 gene signatures between mouse and human are predictive for disease-free survival in human colon, breast and lung adenocarcinoma cancer patients. These results provide novel insights into the role of FBXW7 in tumor development and have identified a number of potential targets for therapeutic intervention.

}, issn = {1949-2553}, doi = {10.18632/oncotarget.6328}, author = {A Snijders and Liu, Yueyong and Su, Li and Huang, Yurong and Jiang-Hua Mao} } @article {224, title = {FBXW7 negatively regulates ENO1 expression and function in colorectal cancer.}, journal = {Lab Invest}, volume = {95}, year = {2015}, month = {2015 Sep}, pages = {995-1004}, abstract = {

FBXW7 (F-box and WD40 domain protein 7) is a tumor suppressor frequently inactivated in human cancers. The precise molecular mechanisms by which FBXW7 exerts antitumor activity remain under intensive investigation and are thought to relate in part to FBXW7-mediated destruction of key cancer-relevant proteins. Enolase 1 (ENO1) possesses oncogenic activity and is often overexpressed in various human cancers, besides its critical role in glycolysis. However, the detailed regulatory mechanisms of ENO1 expression remain unclear. Here we show that the elevated expression of ENO1 was identified in FBXW7-depletion HCT116 cells through two-dimensional protein electrophoresis and mass spectrometry assays (2DE-MS). Subsequent western blotting and immunohistochemical assays confirmed that ENO1 expression reversely correlates with FBXW7 expression in several cells and colon cancer tissues. Furthermore, we show that FBXW7 physically binds to ENO1 and targets ENO1 for ubiquitin-mediated degradation. Functionally, we found that FBXW7 suppresses the ENO1-induced gene expression, lactate production, cell proliferation and migration. These findings suggest that ENO1 is a novel substrate of FBXW7, and its activity can be negatively regulated by FBXW7 at the posttranslational level. Our work provides a novel molecular insight into FBXW7-directed tumor suppression through regulation of ENO1.

}, keywords = {Biomarkers, Tumor, Blotting, Western, Cell Cycle Proteins, Colorectal Neoplasms, DNA Primers, DNA-Binding Proteins, Electrophoresis, Gel, Two-Dimensional, F-Box Proteins, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Immunohistochemistry, Mass Spectrometry, Phosphopyruvate Hydratase, Real-Time Polymerase Chain Reaction, Regression Analysis, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases}, issn = {1530-0307}, doi = {10.1038/labinvest.2015.71}, author = {Zhan, Panpan and Wang, Yuli and Zhao, Shihu and Liu, Chunyan and Wang, Yunshan and Wen, Mingxin and Jiang-Hua Mao and Wei, Guangwei and Zhang, Pengju} } @article {215, title = {Genetic background influences loss of heterozygosity patterns in radiation-induced mouse thymic lymphoma.}, journal = {J Nat Sci}, volume = {1}, year = {2015}, month = {2015}, pages = {e96}, abstract = {

Previous studies have revealed that p53 heterozygous (p53+/-) mice are extremely susceptible to radiation-induced tumorigenesis. To investigate whether genetic background influences radiation induced tumor susceptibility, we crossed p53+/- 129/Sv mice with genetically diverse strains to generate p53+/- F1 hybrids. The results showed that genetic background had a profound impact on tumor latency after exposure to gamma radiation, while the tumor spectrum did not change. We further characterized the thymic lymphomas that arose in the p53+/- mice by genome-wide loss of heterozygosity (LOH) analyses and found that genetic background strongly influenced the frequency of LOH and the loss of which parental allele on different chromosomes. Further research is needed to identify which genetic variations control the LOH patterns in radiation-induced thymic lymphomas and to evaluate its relevance to human cancers.

}, issn = {2377-2700}, author = {Hang, Michael and Huang, Yurong and A Snijders and Jiang-Hua Mao} } @article {214, title = {Genetic Background Modulates lncRNA-Coordinated Tissue Response to Low Dose Ionizing Radiation.}, journal = {Int J Genomics}, volume = {2015}, year = {2015}, month = {2015}, pages = {461038}, abstract = {

Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed after LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs.

}, issn = {2314-436X}, doi = {10.1155/2015/461038}, author = {Tang, Jonathan and Huang, Yurong and Nguyen, David H and Costes, Sylvain V and A Snijders and Jiang-Hua Mao} } @article {229, title = {Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {16247}, abstract = {

Evidence has emerged that suggests a link between motor deficits, obesity and many neurological disorders. However, the contributing genetic risk factors are poorly understood. Here we used the Collaborative Cross (CC), a large panel of newly inbred mice that captures 90\% of the known variation among laboratory mice, to identify the genetic loci controlling rotarod performance and its relationship with body weight in a cohort of 365 mice across 16 CC strains. Body weight and rotarod performance varied widely across CC strains and were significantly negatively correlated. Genetic linkage analysis identified 14 loci that were associated with body weight. However, 45 loci affected rotarod performance, seven of which were also associated with body weight, suggesting a strong link at the genetic level. Lastly, we show that genes identified in this study overlap significantly with those related to neurological disorders and obesity found in human GWA studies. In conclusion, our results provide a genetic framework for studies of the connection between body weight, the central nervous system and behavior.

}, issn = {2045-2322}, doi = {10.1038/srep16247}, author = {Jiang-Hua Mao and Langley, Sasha A and Huang, Yurong and Hang, Michael and Bouchard, Kristofer E and Celniker, Susan E and Brown, James B and Jansson, Janet K and Karpen, Gary H and A Snijders} } @article {219, title = {Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {8919}, abstract = {

The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.

}, keywords = {Animals, Breast Neoplasms, Cell Line, Tumor, Cytokines, Female, Genetic Predisposition to Disease, Mice, Mice, Inbred BALB C, Neoplasms, Radiation-Induced, Quantitative Trait Loci, Risk Factors, Transforming Growth Factor beta1, Tumor Microenvironment}, issn = {2045-2322}, doi = {10.1038/srep08919}, author = {Zhang, Pengju and Lo, Alvin and Huang, Yurong and Huang, Ge and Liang, Guozhou and Mott, Joni and Karpen, Gary H and Blakely, Eleanor A and Bissell, Mina J and Barcellos-Hoff, Mary Helen and A Snijders and Jiang-Hua Mao} } @article {218, title = {Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells.}, journal = {Oncotarget}, volume = {6}, year = {2015}, month = {2015 Feb 28}, pages = {4357-68}, abstract = {

Alterations of the EGFR/ERK and Hippo/YAP pathway have been found in non-small cell lung cancer (NSCLC). Herein, we show that ERK1 and ERK2 have an effect on the Hippo/YAP pathway in human NSCLC cells. Firstly, inhibition of ERK1/2 by siRNA or small-molecular inhibitors decreased the YAP protein level, the reporter activity of the Hippo pathway, and the mRNA levels of the Hippo downstream genes, CTGF, Gli2, and BIRC5. Secondly, degradation of YAP protein was accelerated after ERK1/2 depletion in NSCLC cell lines, in which YAP mRNA level was not decreased. Thirdly, forced over-expression of the ERK2 gene rescued the YAP protein level and Hippo reporter activity after siRNA knockdown targeting 3{\textquoteright}UTR of the ERK2 gene in NSCLC cells. Fourthly, depletion of ERK1/2 reduced the migration and invasion of NSCLC cells. Combined depletion of ERK1/2 had a greater effect on cell migration than depletion of either one separately. Finally, the MEK1/2 inhibitor Trametinib decreased YAP protein level and transcriptional activity of the Hippo pathway in NSCLC cell lines. Our results suggest that ERK1/2 inhibition participates in reducing YAP protein level, which in turn down-regulates expression of the downstream genes of the Hippo pathway to suppress migration and invasion of NSCLC cells.

}, keywords = {Adaptor Proteins, Signal Transducing, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Movement, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lung Neoplasms, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Neoplasm Invasiveness, Phosphoproteins, Protein-Serine-Threonine Kinases, Real-Time Polymerase Chain Reaction, RNA, Small Interfering, Signal Transduction, Transfection}, issn = {1949-2553}, doi = {10.18632/oncotarget.2974}, author = {You, Bin and Yang, Yi-Lin and Xu, Zhidong and Dai, Yuyuan and Liu, Shu and Jiang-Hua Mao and Tetsu, Osamu and Li, Hui and Jablons, David M and You, Liang} } @article {230, title = {Knockdown of Cul4A increases chemosensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells.}, journal = {Oncol Rep}, volume = {34}, year = {2015}, month = {2015 Dec}, pages = {3187-95}, abstract = {

Cullin 4A (Cul4A) promotes oncogenesis through overexpression and then ubiquitination-mediated proteolysis of tumor suppressors in various types of cancers. Transforming growth factor β-induced (TGFBI) has been implicated as a tumor suppressor, which enhances gemcitabine chemosensitivity in lung cancer cells. The present study aimed to investigate the association of TGFBI and Cul4A and the mechanism by which Cul4A regulates TGFBI. In addition, we also evaluated the therapeutic value of Cul4A RNAi using adenoviral transfection of Cul4A RNAi in nude mouse xenograft models. We observed that knockdown of Cul4A was associated with increased sensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells. Cul4A regulated TGFBI through direct interaction and then ubiquitin-mediated protein degradation. In the nude mouse xenograft models, adenoviral transfection of Cul4A RNAi in combination with gemcitabine chemotherapy inhibited lung cancer tumor growth. As the result, combination of Cul4A RNAi with chemotherapy may provide a new approach to lung cancer treatment.

}, keywords = {Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Cullin Proteins, Deoxycytidine, Drug Resistance, Neoplasm, Extracellular Matrix Proteins, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Lung Neoplasms, Mice, Transforming Growth Factor beta, Xenograft Model Antitumor Assays}, issn = {1791-2431}, doi = {10.3892/or.2015.4324}, author = {Hung, Ming-Szu and Chen, I-Chuan and You, Liang and Jablons, David M and Li, Ya-Chin and Jiang-Hua Mao and Xu, Zhidong and Hsieh, Meng-Jer and Lin, Yu-Ching and Yang, Cheng-Ta and Liu, Shin-Tung and Tsai, Ying-Huang} } @article {222, title = {Low-dose radiation cancer susceptibility models.}, journal = {Aging (Albany NY)}, volume = {7}, year = {2015}, month = {2015 Jun}, pages = {352-3}, keywords = {Dose-Response Relationship, Radiation, Genetic Predisposition to Disease, Humans, Models, Biological, Neoplasms, Radiation-Induced, Risk Factors}, issn = {1945-4589}, doi = {10.18632/aging.100767}, author = {Jiang-Hua Mao and A Snijders} } @article {228, title = {Metabolomics reveals metabolic changes in male reproductive cells exposed to thirdhand smoke.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {15512}, abstract = {

Thirdhand smoke (THS) is a new term for the toxins in cigarette smoke that linger in the environment long after the cigarettes are extinguished. The effects of THS exposure on male reproduction have not yet been studied. In this study, metabolic changes in male germ cell lines (GC-2 and TM-4) were analyzed after THS treatment for 24 h. THS-loaded chromatography paper samples were generated in a laboratory chamber system and extracted in DMEM. At a paper: DMEM ratio of 50 μg/ml, cell viability in both cell lines was normal, as measured by the MTT assay and markers of cytotoxicity, cell cycle, apoptosis and ROS production were normal as measured by quantitative immunofluorescence. Metabolomic analysis was performed on methanol extracts of GC-2 and TM-4 cells. Glutathione metabolism in GC-2 cells, and nucleic acid and ammonia metabolism in TM-4 cells, was changed significantly by THS treatment. RT-PCR analyses of mRNA for enzyme genes Gss and Ggt in GC-2 cells, and TK, SMS and Glna in TM-4 cells reinforced these findings, showing changes in the levels of enzymes involved in the relevant pathways. In conclusion, exposure to THS at very low concentrations caused distinct metabolic changes in two different types of male reproductive cell lines.

}, issn = {2045-2322}, doi = {10.1038/srep15512}, author = {Xu, Bo and Chen, Minjian and Yao, Mengmeng and Ji, Xiaoli and Mao, Zhilei and Tang, Wei and Qiao, Shanlei and Schick, Suzaynn F and Jiang-Hua Mao and Hang, Bo and Xia, Yankai} } @article {225, title = {A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development.}, journal = {Oncogene}, volume = {34}, year = {2015}, month = {2015 Sep 3}, pages = {4777-90}, abstract = {

Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load-were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.

}, keywords = {Animals, Apoptosis, Breast Neoplasms, Carcinogenesis, Carrier Proteins, Cell Line, Tumor, Cell Proliferation, Female, Gene Expression Regulation, Neoplastic, Humans, Lactation, Lung Neoplasms, Mammary Glands, Animal, Mice, Mice, Knockout, Pregnancy, Proto-Oncogene Proteins c-akt, STAT3 Transcription Factor, Transcription Factors}, issn = {1476-5594}, doi = {10.1038/onc.2015.224}, author = {Castillo-Lluva, S and Hontecillas-Prieto, L and Blanco-G{\'o}mez, A and Del Mar S{\'a}ez-Freire, M and Garc{\'\i}a-Cenador, B and Garc{\'\i}a-Criado, J and P{\'e}rez-Andr{\'e}s, M and Orfao, A and Ca{\~n}amero, M and Jiang-Hua Mao and Gridley, T and Castellanos-Mart{\'\i}n, A and Perez-Losada, J} } @article {216, title = {Next-Generation Sequencing for Binary Protein-Protein Interactions.}, journal = {Front Genet}, volume = {6}, year = {2015}, month = {2015}, pages = {346}, abstract = {

The yeast two-hybrid (Y2H) system exploits host cell genetics in order to display binary protein-protein interactions (PPIs) via defined and selectable phenotypes. Numerous improvements have been made to this method, adapting the screening principle for diverse applications, including drug discovery and the scale-up for proteome wide interaction screens in human and other organisms. Here we discuss a systematic workflow and analysis scheme for screening data generated by Y2H and related assays that includes high-throughput selection procedures, readout of comprehensive results via next-generation sequencing (NGS), and the interpretation of interaction data via quantitative statistics. The novel assays and tools will serve the broader scientific community to harness the power of NGS technology to address PPI networks in health and disease. We discuss examples of how this next-generation platform can be applied to address specific questions in diverse fields of biology and medicine.

}, issn = {1664-8021}, doi = {10.3389/fgene.2015.00346}, author = {Suter, Bernhard and Zhang, Xinmin and Pesce, C Gustavo and Mendelsohn, Andrew R and Dinesh-Kumar, Savithramma P and Jiang-Hua Mao} } @article {221, title = {PR-Set7 is Degraded in a Conditional Cul4A Transgenic Mouse Model of Lung Cancer.}, journal = {Zhongguo Fei Ai Za Zhi}, volume = {18}, year = {2015}, month = {2015 Jun}, pages = {345-50}, abstract = {

BACKGROUND: Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage.

METHODS: We developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of γ-tubulin and pericentrin by IHC.

RESULTS: The level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre.

CONCLUSIONS: PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.

}, keywords = {Animals, Cell Cycle, Cullin Proteins, Disease Models, Animal, Down-Regulation, Histone-Lysine N-Methyltransferase, Histones, Humans, Lung, Lung Neoplasms, Mice, Mice, Transgenic, Proteolysis, Tubulin}, issn = {1999-6187}, doi = {10.3779/j.issn.1009-3419.2015.06.15}, author = {Wang, Yang and Xu, Zhidong and Jiang-Hua Mao and Hsieh, David and Au, Alfred and Jablons, David M and Li, Hui and You, Liang} } @article {220, title = {[Thirdhand smoke: current research status and future prospects].}, journal = {Zhonghua Yu Fang Yi Xue Za Zhi}, volume = {49}, year = {2015}, month = {2015 Apr}, pages = {295-8}, abstract = {

Thirdhand smoke (THS) is defined as residual tobacco components that remain on indoor surfaces after tobacco has been smoked, such as walls furniture, and dust particles, which are re-emitted into the air. THS also includes secondary pollutants generated from the reaction of surface residual smoke compounds with reactive indoor air pollutants. THS is a new hidden health hazard, with infants and children being most at risk of higher exposure. This article summarized the aging process of secondhand smoke and the mechanism of generation of THS; reviewed the current status of research on THS regarding its chemical constituents, physical and chemical properties, biological toxicity, as well as degree of pollution in China and other countries; and finally provided the perspectives on the future study of THS.

}, keywords = {Adolescent, Air Pollution, Indoor, Child, Child, Preschool, China, Dust, Environmental Exposure, Humans, Infant, Infant, Newborn, Research, Smoke, Tobacco Smoke Pollution}, issn = {0253-9624}, author = {Hang, Bo and Cheng, Senping and Xia, Yankai and Jiang-Hua Mao} } @article {217, title = {Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach.}, journal = {Genome Biol}, volume = {16}, year = {2015}, month = {2015}, pages = {40}, abstract = {

BACKGROUND: An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels.

RESULTS: Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease.

CONCLUSIONS: Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.

}, keywords = {Animals, Breast Neoplasms, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, Mice, Models, Genetic, Neoplasm Metastasis, Proto-Oncogene Proteins c-akt, Receptor, ErbB-2, Systems Biology}, issn = {1474-760X}, doi = {10.1186/s13059-015-0599-z}, author = {Castellanos-Mart{\'\i}n, Andr{\'e}s and Castillo-Lluva, Sonia and S{\'a}ez-Freire, Mar{\'\i}a Del Mar and Blanco-G{\'o}mez, Adri{\'a}n and Hontecillas-Prieto, Lourdes and Patino-Alonso, Carmen and Galindo-Villardon, Purificaci{\'o}n and P{\'e}rez Del Villar, Luis and Mart{\'\i}n-Seisdedos, Carmen and Isidoro-Garcia, Mar{\'\i}a and Abad-Hern{\'a}ndez, Mar{\'\i}a Del Mar and Cruz-Hern{\'a}ndez, Juan Jes{\'u}s and Rodr{\'\i}guez-S{\'a}nchez, C{\'e}sar Augusto and Gonz{\'a}lez-Sarmiento, Rogelio and Alonso-L{\'o}pez, Diego and De Las Rivas, Javier and Garc{\'\i}a-Cenador, Bego{\~n}a and Garc{\'\i}a-Criado, Javier and Lee, Do Yup and Bowen, Benjamin and Reindl, Wolfgang and Northen, Trent and Jiang-Hua Mao and Perez-Losada, Jesus} } @article {206, title = {CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression.}, journal = {Cancer Res}, volume = {74}, year = {2014}, month = {2014 Jan 15}, pages = {520-31}, abstract = {

The ubiquitin ligase CUL4A has been implicated in tumorigenesis, but its contributions to progression and metastasis have not been evaluated. Here, we show that CUL4A is elevated in breast cancer as well as in ovarian, gastric, and colorectal tumors in which its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found that CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis, and metastasis. Furthermore, in human breast cancers, ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells.

}, keywords = {Animals, Breast, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Cullin Proteins, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Histones, Homeodomain Proteins, Humans, Kruppel-Like Transcription Factors, Mammary Neoplasms, Experimental, Mice, Mice, Nude, Neoplasm Metastasis, Neoplasm Transplantation, Promoter Regions, Genetic, Signal Transduction, Transcription Factors}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-13-2182}, author = {Wang, Yunshan and Wen, Mingxin and Kwon, Yongwon and Xu, Yangyang and Liu, Yueyong and Zhang, Pengju and He, Xiuquan and Wang, Qin and Huang, Yurong and Jen, Kuang-Yu and LaBarge, Mark A and You, Liang and Kogan, Scott C and Gray, Joe W and Jiang-Hua Mao and Wei, Guangwei} } @article {211, title = {CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to erlotinib via transcriptional regulation of EGFR.}, journal = {Mol Cancer}, volume = {13}, year = {2014}, month = {2014}, pages = {252}, abstract = {

BACKGROUND: CUL4A has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear.

METHODS: Expression level of CUL4A was examined by RT-PCR and Western blot. Forced expression of CUL4A was mediated by retroviruses, and CUL4A silencing by shRNAs expressing lentiviruses. Growth capacity of lung cancer cells was measured by MTT in vitro and tumorigenesis in vivo, respectively.

RESULTS: We found that CUL4A was highly expressed in human lung cancer tissues and lung cancer cell lines, and this elevated expression positively correlated with disease progression and prognosis. Overexpression of CUL4A in human lung cancer cell lines increased cell proliferation, inhibited apoptosis, and subsequently conferred resistance to chemotherapy. On other hand, silencing CUL4A expression in NSCLC cells reduced proliferation, promoted apoptosis and resulted in tumor growth inhibition in cancer xenograft model. Mechanistically, we revealed CUL4A regulated EGFR transcriptional expression and activation, and subsequently activated AKT. Targeted inhibition of EGFR activity blocked these CUL4A induced oncogenic activities.

CONCLUSIONS: Our results highlight the significance of CUL4A in NSCLC and suggest that CUL4A could be a promising therapy target and a potential biomarker for prognosis and EGFR target therapy in NSCLC patients.

}, keywords = {Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Cullin Proteins, Erlotinib Hydrochloride, Female, Humans, Lung Neoplasms, Male, Middle Aged, Protein Kinase Inhibitors, Quinazolines, Receptor, Epidermal Growth Factor, Transcription, Genetic}, issn = {1476-4598}, doi = {10.1186/1476-4598-13-252}, author = {Wang, Yunshan and Zhang, Pengju and Liu, Ziming and Wang, Qin and Wen, Mingxin and Wang, Yuli and Yuan, Hongtu and Jiang-Hua Mao and Wei, Guangwei} } @article {212, title = {Densely ionizing radiation acts via the microenvironment to promote aggressive Trp53-null mammary carcinomas.}, journal = {Cancer Res}, volume = {74}, year = {2014}, month = {2014 Dec 1}, pages = {7137-48}, abstract = {

Densely ionizing radiation, which is present in the space radiation environment and used in radiation oncology, has potentially greater carcinogenic effect compared with sparsely ionizing radiation that is prevalent on earth. Here, we used a radiation chimera in which mice were exposed to densely ionizing 350 MeV/amu Si-particles, γ-radiation, or sham-irradiated and transplanted 3 days later with syngeneic Trp53-null mammary fragments. Trp53-null tumors arising in mice irradiated with Si-particles had a shorter median time to appearance and grew faster once detected compared with those in sham-irradiated or γ-irradiated mice. Tumors were further classified by markers keratin 8/18 (K18, KRT18), keratin 14 (K14, KRT14) and estrogen receptor (ER, ESR1), and expression profiling. Most tumors arising in sham-irradiated hosts were comprised of both K18- and K14-positive cells (K14/18) while those tumors arising in irradiated hosts were mostly K18. Keratin staining was significantly associated with ER status: K14/18 tumors were predominantly ER-positive, whereas K18 tumors were predominantly ER-negative. Genes differentially expressed in K18 tumors compared with K14/18 tumor were associated with ERBB2 and KRAS, metastasis, and loss of E-cadherin. Consistent with this, K18 tumors tended to grow faster and be more metastatic than K14/18 tumors, however, K18 tumors in particle-irradiated mice grew significantly larger and were more metastatic compared with sham-irradiated mice. An expression profile that distinguished K18 tumors arising in particle-irradiated mice compared with sham-irradiated mice was enriched in mammary stem cell, stroma, and Notch signaling genes. These data suggest that carcinogenic effects of densely ionizing radiation are mediated by the microenvironment, which elicits more aggressive tumors compared with similar tumors arising in sham-irradiated hosts.

}, keywords = {Animals, Biomarkers, Tumor, Cadherins, Female, Gene Expression Profiling, Keratins, Mammary Neoplasms, Experimental, Mice, Mice, Inbred BALB C, Proto-Oncogene Proteins p21(ras), Radiation, Ionizing, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Notch, Stem Cells, Tumor Microenvironment, Tumor Suppressor Protein p53}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-14-1212}, author = {Illa-Bochaca, Irineu and Ouyang, Haoxu and Tang, Jonathan and Sebastiano, Christopher and Jiang-Hua Mao and Costes, Sylvain V and Demaria, Sandra and Barcellos-Hoff, Mary Helen} } @article {213, title = {Distinct luminal-type mammary carcinomas arise from orthotopic Trp53-null mammary transplantation of juvenile versus adult mice.}, journal = {Cancer Res}, volume = {74}, year = {2014}, month = {2014 Dec 1}, pages = {7149-58}, abstract = {

Age and physiologic status, such as menopause, are risk factors for breast cancer. Less clear is what factors influence the diversity of breast cancer. In this study, we investigated the effect of host age on the distribution of tumor subtypes in mouse mammary chimera consisting of wild-type hosts and Trp53 nullizygous epithelium, which undergoes a high rate of neoplastic transformation. Wild-type mammary glands cleared of endogenous epithelium at 3 weeks of age were subsequently transplanted during puberty (5 weeks) or at maturation (10 weeks) with syngeneic Trp53-null mammary tissue fragments and monitored for one year. Tumors arose sooner from adult hosts (AH) compared with juvenile hosts (JH). However, compared with AH tumors, JH tumors grew several times faster, were more perfused, exhibited a two-fold higher mitotic index, and were more highly positive for insulin-like growth factor receptor phosphorylation. Most tumors in each setting were estrogen receptor (ER)-positive (80\% JH vs. 70\% AH), but JH tumors were significantly more ER-immunoreactive (P = 0.0001) than AH tumors. A differential expression signature (JvA) of juvenile versus adult tumors revealed a luminal transcriptional program. Centroids of the human homologs of JvA genes showed that JH tumors were more like luminal A tumors and AH tumors were more like luminal B tumors. Hierarchical clustering with the JvA human ortholog gene list segregated luminal A and luminal B breast cancers across datasets. These data support the notion that age-associated host physiology greatly influences the intrinsic subtype of breast cancer.

}, keywords = {Animals, Breast Neoplasms, Cell Transformation, Neoplastic, Cluster Analysis, Epithelium, Female, Gene Expression Regulation, Neoplastic, Humans, Mammary Glands, Human, Mammary Neoplasms, Experimental, Mice, Mice, Inbred BALB C, Phosphorylation, Receptors, Estrogen, Receptors, Somatomedin, Tumor Suppressor Protein p53}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-14-1440}, author = {Nguyen, David H and Ouyang, Haoxu and Jiang-Hua Mao and Hlatky, Lynn and Barcellos-Hoff, Mary Helen} } @article {210, title = {Expression quantitative trait loci and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma.}, journal = {Cell Rep}, volume = {9}, year = {2014}, month = {2014 Nov 6}, pages = {1034-46}, abstract = {

The development of targeted therapeutics for neuroblastoma, the third most common tumor in children, has been limited by a poor understanding of growth signaling mechanisms unique to the peripheral nerve precursors from which tumors arise. In this study, we combined genetics with gene-expression analysis in the peripheral sympathetic nervous system to implicate arginase 1 and GABA signaling in tumor formation in vivo. In human neuroblastoma cells, either blockade of ARG1 or benzodiazepine-mediated activation of GABA-A receptors induced apoptosis and inhibited mitogenic signaling through AKT and MAPK. These results suggest that ARG1 and GABA influence both neural development and neuroblastoma and that benzodiazepines in clinical use may have potential applications for neuroblastoma therapy.

}, keywords = {Animals, Apoptosis, Arginase, Brain Neoplasms, Cell Line, Tumor, Cell Survival, Chromosomes, Mammalian, gamma-Aminobutyric Acid, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Linkage, Genetic Predisposition to Disease, Humans, Mice, Molecular Targeted Therapy, Neuroblastoma, Quantitative Trait Loci, Receptors, GABA-A, Survival Analysis}, issn = {2211-1247}, doi = {10.1016/j.celrep.2014.09.046}, author = {Hackett, Christopher S and Quigley, David A and Wong, Robyn A and Chen, Justin and Cheng, Christine and Song, Young K and Wei, Jun S and Pawlikowska, Ludmila and Bao, Yun and Goldenberg, David D and Nguyen, Kim and Gustafson, W Clay and Rallapalli, Sundari K and Cho, Yoon-Jae and Cook, James M and Kozlov, Serguei and Jiang-Hua Mao and Van Dyke, Terry and Kwok, Pui-Yan and Khan, Javed and Balmain, Allan and Fan, QiWen and Weiss, William A} } @article {209, title = {An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival.}, journal = {Oncotarget}, volume = {5}, year = {2014}, month = {2014 Jun 30}, pages = {4011-25}, abstract = {

The concept that a breast cancer patient{\textquoteright}s menstrual stage at the time of tumor surgery influences risk of metastases remains controversial. The scarcity of comprehensive molecular studies of menstrual stage-dependent fluctuations in the breast provides little insight in this observation. To gain a deeper understanding of the biological changes in mammary tissue and blood during the menstrual cycle and to determine the influence of environmental exposures, such as low-dose ionizing radiation (LDIR), we used the mouse to characterize estrous-cycle variations in mammary gene transcripts by RNA-sequencing, peripheral white blood cell (WBC) counts and plasma cytokine levels. We identified an estrous-variable and hormone-dependent gene cluster enriched for Type-1 interferon genes. Cox regression identified a 117-gene signature of interferon-associated genes, which correlated with lower frequencies of metastasis in breast cancer patients. LDIR (10cGy) exposure had no detectable effect on mammary transcripts. However, peripheral WBC counts varied across the estrous cycle and LDIR exposure reduced lymphocyte counts and cytokine levels in tumor-susceptible mice. Our finding of variations in mammary Type-1 interferon and immune functions across the estrous cycle provides a mechanism by which timing of breast tumor surgery during the menstrual cycle may have clinical relevance to a patient{\textquoteright}s risk for distant metastases.

}, keywords = {Animals, Disease-Free Survival, Estrous Cycle, Female, Humans, Interferons, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Metastasis, RNA, Messenger}, issn = {1949-2553}, doi = {10.18632/oncotarget.2148}, author = {A Snijders and Langley, Sasha and Jiang-Hua Mao and Bhatnagar, Sandhya and Bjornstad, Kathleen A and Rosen, Chris J and Lo, Alvin and Huang, Yurong and Blakely, Eleanor A and Karpen, Gary H and Bissell, Mina J and Wyrobek, Andrew J} } @article {207, title = {Irradiation of juvenile, but not adult, mammary gland increases stem cell self-renewal and estrogen receptor negative tumors.}, journal = {Stem Cells}, volume = {32}, year = {2014}, month = {2014 Mar}, pages = {649-61}, abstract = {

Children exposed to ionizing radiation have a substantially greater breast cancer risk than adults; the mechanism for this strong age dependence is not known. Here we show that pubertal murine mammary glands exposed to sparsely or densely ionizing radiation exhibit enrichment of mammary stem cell and Notch pathways, increased mammary repopulating activity indicative of more stem cells, and propensity to develop estrogen receptor (ER) negative tumors thought to arise from stem cells. We developed a mammary lineage agent-based model (ABM) to evaluate cell inactivation, self-renewal, or dedifferentiation via epithelial-mesenchymal transition (EMT) as mechanisms by which radiation could increase stem cells. ABM rejected cell inactivation and predicted increased self-renewal would only affect juveniles while dedifferentiation could act in both juveniles and adults. To further test self-renewal versus dedifferentiation, we used the MCF10A human mammary epithelial cell line, which recapitulates ductal morphogenesis in humanized fat pads, undergoes EMT in response to radiation and transforming growth factor β (TGFβ) and contains rare stem-like cells that are Let-7c negative or express both basal and luminal cytokeratins. ABM simulation of population dynamics of double cytokeratin cells supported increased self-renewal in irradiated MCF10A treated with TGFβ. Radiation-induced Notch concomitant with TGFβ was necessary for increased self-renewal of Let-7c negative MCF10A cells but not for EMT, indicating that these are independent processes. Consistent with these data, irradiating adult mice did not increase mammary repopulating activity or ER-negative tumors. These studies suggest that irradiation during puberty transiently increases stem cell self-renewal, which increases susceptibility to developing ER-negative breast cancer.

}, keywords = {Aging, Animals, Biomarkers, Cell Line, Cell Lineage, Cell Proliferation, Computer Simulation, Dose-Response Relationship, Radiation, Epithelial Cells, Female, Humans, Mammary Glands, Animal, Mammary Neoplasms, Animal, Mice, Morphogenesis, Radiation, Ionizing, Receptors, Estrogen, Receptors, Notch, Stem Cells, Transforming Growth Factor beta}, issn = {1549-4918}, doi = {10.1002/stem.1533}, author = {Tang, Jonathan and Fernandez-Garcia, Ignacio and Vijayakumar, Sangeetha and Martinez-Ruis, Haydeliz and Illa-Bochaca, Irineu and Nguyen, David H and Jiang-Hua Mao and Costes, Sylvain V and Barcellos-Hoff, Mary Helen} } @article {208, title = {Lung tumourigenesis in a conditional Cul4A transgenic mouse model.}, journal = {J Pathol}, volume = {233}, year = {2014}, month = {2014 Jun}, pages = {113-23}, abstract = {

Cullin4A (Cul4A) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes and regulates many cellular events, including cell survival, development, growth and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumour development. After Cul4A over-expression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumours were visible and were characterized as grade I or II adenocarcinomas. Immunohistochemistry (IHC) revealed decreased levels of Cul4A-associated proteins p21(CIP1) and tumour suppressor p19(ARF) in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27(KIP1) and p16(INK4a) were also detected in these tumours. Moreover, the protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumours was further analysed by the results from pericentrin protein expression and array comparative genomic hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro, suggesting that Cul4A over-expression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo, and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.

}, keywords = {Adenocarcinoma, Animals, Antineoplastic Agents, Cell Cycle Proteins, Cell Line, Tumor, Cell Survival, Cell Transformation, Neoplastic, Cisplatin, Cullin Proteins, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p19, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Disease Models, Animal, DNA-Binding Proteins, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Genomic Instability, Humans, Lung, Lung Neoplasms, Mice, Mice, Transgenic, Neoplasm Grading, Proliferating Cell Nuclear Antigen, RNA Interference, Time Factors, Transfection, Up-Regulation}, issn = {1096-9896}, doi = {10.1002/path.4352}, author = {Yang, Yi-Lin and Hung, Ming-Szu and Wang, Yang and Ni, Jian and Jiang-Hua Mao and Hsieh, David and Au, Alfred and Kumar, Atul and Quigley, David and Fang, Li Tai and Yeh, Che-Chung and Xu, Zhidong and Jablons, David M and You, Liang} } @article {198, title = {A 12-gene set predicts survival benefits from adjuvant chemotherapy in non-small cell lung cancer patients.}, journal = {Clin Cancer Res}, volume = {19}, year = {2013}, month = {2013 Mar 15}, pages = {1577-86}, abstract = {

PURPOSE: Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for non-small cell lung cancer (NSCLC) patients. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefits of ACT in NSCLC.

EXPERIMENTAL DESIGN: An 18-hub-gene prognosis signature was developed through a systems biology approach, and its prognostic value was evaluated in six independent cohorts. The 18-hub-gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a 12-gene predictive signature for ACT benefits in NSCLC.

RESULTS: Using a cohort of 442 stage I to III NSCLC patients who underwent surgical resection, we identified an 18-hub-gene set that robustly predicted the prognosis of patients with adenocarcinoma in all validation datasets across four microarray platforms. The hub genes, identified through a purely data-driven approach, have significant biological implications in tumor pathogenesis, including NKX2-1, Aurora Kinase A, PRC1, CDKN3, MBIP, and RRM2. The 12-gene predictive signature was successfully validated in two independent datasets (n = 90 and 176). The predicted benefit group showed significant improvement in survival after ACT (UT Lung SPORE data: HR = 0.34, P = 0.017; JBR.10 clinical trial data: HR = 0.36, P = 0.038), whereas the predicted nonbenefit group showed no survival benefit for 2 datasets (HR = 0.80, P = 0.70; HR = 0.91, P = 0.82).

CONCLUSIONS: This is the first study to integrate genetic aberration, genome-wide RNAi data, and mRNA expression data to identify a functional gene set that predicts which resectable patients with non-small cell lung cancer will have a survival benefit with ACT.

}, keywords = {Adult, Aged, Carcinoma, Non-Small-Cell Lung, Chemotherapy, Adjuvant, Clinical Trials as Topic, Female, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, Kaplan-Meier Estimate, Lung Neoplasms, Male, Middle Aged, Neoplasm Proteins, Neoplasm Staging, Prognosis, RNA Interference, Systems Biology, Treatment Outcome}, issn = {1078-0432}, doi = {10.1158/1078-0432.CCR-12-2321}, author = {Tang, Hao and Xiao, Guanghua and Behrens, Carmen and Schiller, Joan and Allen, Jeffrey and Chow, Chi-Wan and Suraokar, Milind and Corvalan, Alejandro and Jiang-Hua Mao and White, Michael A and Wistuba, Ignacio I and Minna, John D and Xie, Yang} } @article {202, title = {C2ORF40 suppresses breast cancer cell proliferation and invasion through modulating expression of M phase cell cycle genes.}, journal = {Epigenetics}, volume = {8}, year = {2013}, month = {2013 Jun}, pages = {571-83}, abstract = {

Recently, it has been suggested that C2ORF40 is a candidate tumor suppressor gene in breast cancer. However, the mechanism for reduced expression of C2ORF40 and its functional role in breast cancers remain unclear. Here we show that C2ORF40 is frequently silenced in human primary breast cancers and cell lines through promoter hypermethylation. C2ORF40 mRNA level is significantly associated with patient disease-free survival and distant cancer metastasis. Overexpression of C2ORF4 0 inhibits breast cancer cell proliferation, migration and invasion. By contrast, silencing C2ORF40 expression promotes these biological phenotypes. Bioinformatics and FACS analysis reveal C2ORF40 functions at G2/M phase by downregulation of mitotic genes expression, including UBE2C. Our results suggest that C2ORF40 acts as a tumor suppressor gene in breast cancer pathogenesis and progression and is a candidate prognostic marker for this disease.

}, keywords = {Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, DNA Methylation, Female, Gene Expression Regulation, Neoplastic, Genes, cdc, Genes, Tumor Suppressor, Humans, Mitosis, Neoplasm Invasiveness, Neoplasm Proteins, Prognosis}, issn = {1559-2308}, doi = {10.4161/epi.24626}, author = {Lu, Jing and Wen, Mingxin and Huang, Yurong and He, Xiuquan and Wang, Yunshan and Wu, Qi and Li, Zengchun and Castellanos-Mart{\'\i}n, Andr{\'e}s and Abad, Mar and Cruz-Hernandez, Juan J and Rodriguez, Cesar A and Perez-Losada, Jesus and Jiang-Hua Mao and Wei, Guangwei} } @article {205, title = {FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7.}, journal = {Oncotarget}, volume = {4}, year = {2013}, month = {2013 Dec}, pages = {2476-86}, abstract = {

Amplification of chromosome 20q is frequently found in various types of human cancers, including breast cancer. The list of candidate oncogenes in 20q has expanded over the past decade. Here, we investigate whether FAM83D (family with sequence similarity 83, member D) on chromosome 20q plays any role in breast cancer development. The expression level of FAM83D is significantly elevated in breast cancer cell lines and primary human breast cancers. High expression levels of FAM83D are significantly associated with poor clinical outcome and distant metastasis in breast cancer patients. We show that ectopic expression of FAM83D in human mammary epithelial cells promotes cell proliferation, migration and invasion along with epithelial-mesenchymal transition (EMT). Ablation of FAM83D in breast cancer cells induces apoptosis and consequently inhibits cell proliferation and colony formation. Mechanistic studies reveal that overexpression of FAM83D downregulates FBXW7 expression levels through a physical interaction, which results in elevated protein levels of oncogenic substrates downstream to FBXW7, such as mTOR, whose inhibition by rapamycin can suppress FAM83D-induced cell migration and invasion. The results demonstrate that FAM83D has prognostic value for breast cancer patients and is a novel oncogene in breast cancer development that at least in part acts through mTOR hyper-activation by inhibiting FBXW7.

}, keywords = {Apoptosis, Breast Neoplasms, Cell Cycle Proteins, Cell Growth Processes, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, Down-Regulation, Epithelial-Mesenchymal Transition, F-Box Proteins, Genes, Tumor Suppressor, Humans, Microtubule-Associated Proteins, Prognosis, Transfection, Ubiquitin-Protein Ligases}, issn = {1949-2553}, doi = {10.18632/oncotarget.1581}, author = {Wang, Zeran and Liu, Yueyong and Zhang, Pengju and Zhang, Weiguo and Wang, Weijing and Curr, Kenneth and Wei, Guangwei and Jiang-Hua Mao} } @article {204, title = {Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model.}, journal = {Int J Oncol}, volume = {43}, year = {2013}, month = {2013 Nov}, pages = {1517-22}, abstract = {

Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer cell growth, Akt/PKB Ser129 phosphorylation, the Wnt/TCF pathway and increased apoptosis. In a murine xenograft model of lung cancer, hematein inhibited tumor growth without significant toxicity to the mice tested. Molecular docking showed that hematein binds to CK2α in durable binding sites. Collectively, our results suggest that hematein is an allosteric inhibitor of protein kinase CK2 and has antitumor activity to lung cancer.

}, keywords = {Animals, Apoptosis, Blotting, Western, Casein Kinase II, Enzyme Inhibitors, Female, Hematoxylin, Humans, Immunoenzyme Techniques, Lung Neoplasms, Mice, Mice, Inbred BALB C, Phosphorylation, Proto-Oncogene Proteins c-akt, T Cell Transcription Factor 1, Tumor Cells, Cultured, Wnt Proteins, Xenograft Model Antitumor Assays}, issn = {1791-2423}, doi = {10.3892/ijo.2013.2087}, author = {Hung, Ming-Szu and Xu, Zhidong and Chen, Yu and Smith, Emmanuel and Jiang-Hua Mao and Hsieh, David and Lin, Yu-Ching and Yang, Cheng-Ta and Jablons, David M and You, Liang} } @article {194, title = {Mass spectrometry imaging for in situ kinetic histochemistry.}, journal = {Sci Rep}, volume = {3}, year = {2013}, month = {2013}, pages = {1656}, abstract = {

Tissues are composed of diverse cell subpopulations each with distinct metabolic characteristics that influence overall behavior. Unfortunately, traditional histopathology imaging techniques are {\textquoteright}blind{\textquoteright} to the spatially ordered metabolic dynamics within tissue. While mass spectrometry imaging enables spatial mapping of molecular composition, resulting images are only a static snapshot in time of molecules involved in highly dynamic processes; kinetic information of flux through metabolic pathways is lacking. To address this limitation, we developed kinetic mass spectrometry imaging (kMSI), a novel technique integrating soft desorption/ionization mass spectrometry with clinically accepted in vivo metabolic labeling of tissue with deuterium to generate images of kinetic information of biological processes. Applied to a tumor, kMSI revealed heterogeneous spatial distributions of newly synthesized versus pre-existing lipids, with altered lipid synthesis patterns distinguishing region-specific intratumor subpopulations. Images also enabled identification and correlation of metabolic activity of specific lipids found in tumor regions of varying grade.

}, keywords = {Cell Line, Tumor, Equipment Design, Equipment Failure Analysis, Humans, Lipids, Mass Spectrometry, Molecular Imaging, Neoplasms, Experimental}, issn = {2045-2322}, doi = {10.1038/srep01656}, author = {Louie, Katherine B and Bowen, Benjamin P and McAlhany, Stephanie and Huang, Yurong and Price, John C and Jiang-Hua Mao and Hellerstein, Marc and Northen, Trent R} } @article {197, title = {Meta-analysis of Aurora Kinase A (AURKA) Expression Data Reveals a Significant Correlation Between Increased AURKA Expression and Distant Metastases in Human ER-positive Breast Cancers.}, journal = {J Data Mining Genomics Proteomics}, volume = {4}, year = {2013}, month = {2013 Mar 6}, pages = {127}, issn = {2153-0602}, doi = {10.4172/2153-0602.1000127}, author = {Weier, Heinz-Ulli G and Jiang-Hua Mao} } @article {199, title = {Murine microenvironment metaprofiles associate with human cancer etiology and intrinsic subtypes.}, journal = {Clin Cancer Res}, volume = {19}, year = {2013}, month = {2013 Mar 15}, pages = {1353-62}, abstract = {

PURPOSE: Ionizing radiation is a well-established carcinogen in rodent models and a risk factor associated with human cancer. We developed a mouse model that captures radiation effects on host biology by transplanting unirradiated Trp53-null mammary tissue to sham or irradiated hosts. Gene expression profiles of tumors that arose in irradiated mice are distinct from those that arose in na{\"\i}ve hosts. We asked whether expression metaprofiles could discern radiation-preceded human cancer or be informative in sporadic breast cancers.

EXPERIMENTAL DESIGN: Affymetrix microarray gene expression data from 56 Trp53-null mammary tumors were used to define gene profiles and a centroid that discriminates tumors arising in irradiated hosts. These were applied to publicly available human cancer datasets.

RESULTS: Host irradiation induces a metaprofile consisting of gene modules representing stem cells, cell motility, macrophages, and autophagy. Human orthologs of the host irradiation metaprofile discriminated between radiation-preceded and sporadic human thyroid cancers. An irradiated host centroid was strongly associated with estrogen receptor-negative breast cancer. When applied to sporadic human breast cancers, the irradiated host metaprofile strongly associated with basal-like and claudin-low breast cancer intrinsic subtypes. Comparing host irradiation in the context of TGF-β levels showed that inflammation was robustly associated with claudin-low tumors.

CONCLUSIONS: Detection of radiation-preceded human cancer by the irradiated host metaprofile raises possibilities of assessing human cancer etiology. Moreover, the association of the irradiated host metaprofiles with estrogen receptor-negative status and claudin-low subtype suggests that host processes similar to those induced by radiation underlie sporadic cancers.

}, keywords = {Animals, Breast Neoplasms, Female, Gene Expression Regulation, Neoplastic, Humans, Mammary Neoplasms, Animal, Mice, Radiation, Ionizing, Transcriptome, Tumor Microenvironment, Tumor Suppressor Protein p53}, issn = {1078-0432}, doi = {10.1158/1078-0432.CCR-12-3554}, author = {Nguyen, David H and Fredlund, Erik and Zhao, Wei and Perou, Charles M and Balmain, Allan and Jiang-Hua Mao and Barcellos-Hoff, Mary Helen} } @article {203, title = {The prostate cancer-up-regulated long noncoding RNA PlncRNA-1 modulates apoptosis and proliferation through reciprocal regulation of androgen receptor.}, journal = {Urol Oncol}, volume = {31}, year = {2013}, month = {2013 Oct}, pages = {1117-23}, abstract = {

OBJECTIVE: Emerging evidences implicate long noncoding RNAs (lncRNAs) are deregulated in cancer development. The purpose of the current study is to investigate the role of new lncRNA, named PlncRNA-1, in prostate cancer (CaP) pathogenesis.

MATERIALS AND METHODS: In this study, real-time q-PCR was used to demonstrate the expression of PlncRNA-1 in 16 pairs CaP tissues and matched normal tissues, 14 pairs CaP tissues and BPH tissues, 4 CaP cell lines, including LNCaP, LNCaP-AI, PC3, and C4-2, and 2 normal prostate epithelial cell lines RWPE-1 and PWR-1E. After PlncRNA-1 was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, cell proliferation and apoptosis were assessed using CCK-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). After PlncRNA-1 and AR was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, real-time q-PCR and Western blotting were used to measure reciprocal regulation of PlncRNA-1 and AR.

RESULTS: We showed that expression PlncRNA-1, was significantly higher in CaP cells relative to normal prostate epithelial cells, as well as higher in human CaPs compared with normal tissues and benign prostatic hyperplasia (BPH). Silencing of PlncRNA-1 significantly reduced cell proliferation and induced apoptosis in CaP cell lines LNCaP and LNCaP-AI. Mechanistically, PlncRNA-1 suppression by siRNA resulted in a decrease of androgen receptor (AR) mRNA, protein and AR downstream target. Of note, blockade of AR signaling with siRNA also resulted in a suppression of PlncRNA-1 expression in CaP cell lines.

CONCLUSIONS: Our study suggests reciprocal regulation of PlncRNA-1 and androgen receptor contribute to CaP pathogenesis and that PlncRNA-1 is a potential therapy target.

}, keywords = {Apoptosis, Base Sequence, Blotting, Western, Cell Line, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Male, Molecular Sequence Data, Prostatic Neoplasms, Receptors, Androgen, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, RNA, Long Noncoding, Up-Regulation}, issn = {1873-2496}, doi = {10.1016/j.urolonc.2011.11.030}, author = {Cui, Zilian and Ren, Shancheng and Lu, Ji and Wang, Fubo and Xu, Weidong and Sun, Yi and Wei, Min and Chen, Junyi and Gao, Xu and Xu, Chuanliang and Jiang-Hua Mao and Sun, Yinghao} } @article {200, title = {Ptch1 overexpression drives skin carcinogenesis and developmental defects in K14Ptch(FVB) mice.}, journal = {J Invest Dermatol}, volume = {133}, year = {2013}, month = {2013 May}, pages = {1311-20}, abstract = {

Ptch1 is a key regulator of embryonic development, acting through the sonic hedgehog (SHH) signaling pathway. Ptch1 is best known as a tumor suppressor, as germline or somatic mutations in Ptch1 lead to the formation of skin basal cell carcinomas. Here we show that Ptch1 also acts as a lineage-dependent oncogene, as overexpression of Ptch1 in adult skin in K14Ptch(FVB) transgenic mice synergizes with chemically induced Hras mutations to promote squamous carcinoma development. These effects were not because of aberrant activation of SHH signaling by the K14Ptch(FVB) transgene, as developmental defects in the highest expressing transgenic lines were consistent with the inhibition of this pathway. Carcinomas from K14Ptch(FVB) transgenic mice had only a small number of nonproliferative Ptch1 transgene-positive cells, suggesting that the Ptch1 transgene is not required for tumor maintenance, but may have a critical role in cell-fate determination at the initiation stage.

}, keywords = {9,10-Dimethyl-1,2-benzanthracene, Animals, Carcinoma, Squamous Cell, Disease Models, Animal, Fetal Development, Gene Expression Regulation, Neoplastic, Hedgehog Proteins, Keratin-14, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Proto-Oncogene Proteins p21(ras), Receptors, Cell Surface, Signal Transduction, Skin Neoplasms, Transgenes}, issn = {1523-1747}, doi = {10.1038/jid.2012.419}, author = {Kang, Hio Chung and Wakabayashi, Yuichi and Jen, Kuang-Yu and Jiang-Hua Mao and Zoumpourlis, Vassilis and Del Rosario, Reyno and Balmain, Allan} } @article {201, title = {Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells.}, journal = {Biochem Biophys Res Commun}, volume = {434}, year = {2013}, month = {2013 May 3}, pages = {352-6}, abstract = {

Increased cell migration and invasion lead to cancer metastasis and are crucial to cancer prognosis. In this study, we explore whether FBXW7 plays any role in metastatic process. We show that depletion of FBXW7 induces epithelial-mesenchymal transition (EMT) in human colon cancer cells along with the increase in cell migration and invasion. Moreover, FBXW7 deficiency promotes the generation of colon cancer stem-like cells in tumor-sphere culture. mTOR inhibition by rapamycin suppresses FBXW7 loss-driven EMT, invasion and stemness. Our results define the FBXW7/mTOR axis as a novel EMT pathway that mediates cancer invasion.

}, keywords = {Blotting, Western, Cell Cycle Proteins, Cell Movement, Cell Shape, Colorectal Neoplasms, Epithelial-Mesenchymal Transition, F-Box Proteins, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Neoplasm Invasiveness, Neoplastic Stem Cells, Sirolimus, TOR Serine-Threonine Kinases, Ubiquitin-Protein Ligases}, issn = {1090-2104}, doi = {10.1016/j.bbrc.2013.03.077}, author = {Wang, Yuli and Liu, Yueyong and Lu, Jing and Zhang, Pengju and Wang, Yunshan and Xu, Yangyang and Wang, Zeran and Jiang-Hua Mao and Wei, Guangwei} } @article {195, title = {Rewiring of human lung cell lineage and mitotic networks in lung adenocarcinomas.}, journal = {Nat Commun}, volume = {4}, year = {2013}, month = {2013}, pages = {1701}, abstract = {

Analysis of gene expression patterns in normal tissues and their perturbations in tumours can help to identify the functional roles of oncogenes or tumour suppressors and identify potential new therapeutic targets. Here, gene expression correlation networks were derived from 92 normal human lung samples and patient-matched adenocarcinomas. The networks from normal lung show that NKX2-1 is linked to the alveolar type 2 lineage, and identify PEBP4 as a novel marker expressed in alveolar type 2 cells. Differential correlation analysis shows that the NKX2-1 network in tumours includes pathways associated with glutamate metabolism, and identifies Vaccinia-related kinase (VRK1) as a potential drug target in a tumour-specific mitotic network. We show that VRK1 inhibition cooperates with inhibition of poly (ADP-ribose) polymerase signalling to inhibit growth of lung tumour cells. Targeting of genes that are recruited into tumour mitotic networks may provide a wider therapeutic window than that seen by inhibition of known mitotic genes.

}, keywords = {Adenocarcinoma, Cell Lineage, Gene Expression Profiling, Humans, Lung, Lung Neoplasms, Mitosis}, issn = {2041-1723}, doi = {10.1038/ncomms2660}, author = {Kim, Il-Jin and Quigley, David and To, Minh D and Pham, Patrick and Lin, Kevin and Jo, Brian and Jen, Kuang-Yu and Raz, Dan and Kim, Jae and Jiang-Hua Mao and Jablons, David and Balmain, Allan} } @article {196, title = {Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development.}, journal = {Aging (Albany NY)}, volume = {5}, year = {2013}, month = {2013 Feb}, pages = {111-9}, abstract = {

FBXW7 acts as a tumor suppressor in numerous types of human cancers through ubiquitination of different oncoproteins including mTOR. However, how the mutation/loss of Fbxw7 results in tumor development remains largely unknown. Here we report that downregulation of mTOR by radiation is Fbxw7-dependent, and short-term mTOR inhibition by rapamycin after exposure to radiation significantly postpones tumor development in Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice but not in p53 single heterozygous (p53+/-) mice. Tumor latency of rapamycin treated Fbxw7+/-p53+/- mice is remarkably similar to those of p53+/- mice while placebo treatedFbxw7+/-p53+/- mice develop tumor significantly earlier than placebo treated p53+/- mice. Furthermore, we surprisingly find that, although temporal treatment of rapamycin is given at a young age, the inhibition of mTOR activity sustainably remains in tumors. These results indicate that inhibition of mTOR signaling pathway suppresses the contribution of Fbxw7 loss toward tumor development.

}, keywords = {Animals, Cell Transformation, Neoplastic, F-Box Proteins, Genes, Tumor Suppressor, Mice, Mutation, Neoplasms, Radiation-Induced, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Ubiquitin-Protein Ligases}, issn = {1945-4589}, doi = {10.18632/aging.100535}, author = {Liu, Yueyong and Huang, Yurong and Wang, Zeran and Huang, Yong and Li, Xiaohua and Louie, Alexander and Wei, Guangwei and Jiang-Hua Mao} } @article {180, title = {Allele-specific deletions in mouse tumors identify Fbxw7 as germline modifier of tumor susceptibility.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e31301}, abstract = {

Genome-wide association studies (GWAS) have been successful in finding associations between specific genetic variants and cancer susceptibility in human populations. These studies have identified a range of highly statistically significant associations between single nucleotide polymorphisms (SNPs) and susceptibility to development of a range of human tumors. However, the effect of each SNP in isolation is very small, and all of the SNPs combined only account for a relatively minor proportion of the total genetic risk (5-10\%). There is therefore a major requirement for alternative routes to the discovery of genetic risk factors for cancer. We have previously shown using mouse models that chromosomal regions harboring susceptibility genes identified by linkage analysis frequently exhibit allele-specific genetic alterations in tumors. We demonstrate here that the Fbxw7 gene, a commonly mutated gene in a wide range of mouse and human cancers, shows allele-specific deletions in mouse lymphomas and skin tumors. Lymphomas from three different F1 hybrids show 100\% allele-specificity in the patterns of allelic loss. Parental alleles from 129/Sv or Spretus/Gla mice are lost in tumors from F1 hybrids with C57BL/6 animals, due to the presence of a specific non-synonymous coding sequence polymorphism at the N-terminal portion of the gene. A specific genetic test of association between this SNP and lymphoma susceptibility in interspecific backcross mice showed a significant linkage (p = 0.001), but only in animals with a functional p53 gene. These data therefore identify Fbxw7 as a p53-dependent tumor susceptibility gene. Increased p53-dependent tumor susceptibility and allele-specific losses were also seen in a mouse skin model of skin tumor development. We propose that analysis of preferential allelic imbalances in tumors may provide an efficient means of uncovering genetic variants that affect mouse and human tumor susceptibility.

}, keywords = {Alleles, Animals, F-Box Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Lymphoma, Mice, Neoplasms, Sequence Deletion, Skin Neoplasms, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0031301}, author = {Perez-Losada, Jesus and Wu, Di and DelRosario, Reyno and Balmain, Allan and Jiang-Hua Mao} } @article {187, title = {Development of a rapid and practical mutation screening assay for human lung adenocarcinoma.}, journal = {Int J Oncol}, volume = {40}, year = {2012}, month = {2012 Jun}, pages = {1900-6}, abstract = {

Mortality after initial diagnosis of lung cancer is higher than from any other cancer. Although mutations in several genes, such as EGFR and K-ras, have been associated with clinical outcome, technical complexity, cost and time have rendered routine screening prohibitive for most lung cancer patients prior to treatment. In this study, using both novel and established technologies, we developed a clinically practical assay to survey the status of three frequently mutated genes in lung cancer (EGFR, K-ras and TP53) and two genes (BRAF and β-catenin) with known hotspot mutations in many other cancers. A single 96-well plate was designed targeting a total of 14 fragments (16 exons) from EGFR, K-ras, TP53, BRAF and β-catenin. In 96 lung adenocarcinoma patients, the mutation frequencies of three major genes (EGFR, K-ras and TP53) were between 21-24\%. Fifty-six out of 96 (58\%) patients had a mutation in at least one of the five genes. K-ras mutations positively correlated with smoking pack-years (p=0.035). EGFR mutations were frequent in never-smokers (p=0.0007), Asians (p=0.0204) and non-stage I lung cancer (p=0.016). There was also a trend towards an association between the presence of any mutation and improved recurrence-free survival (p=0.070). We demonstrate that our novel multigene mutation assay technology can rapidly and cost-effectively screen for mutations in lung adenocarcinoma. This screening assay can be used in the clinical setting for the large-scale validation of prognosis and/or predicting therapeutic response so that the majority of lung cancer patients can benefit from leveraging up-to-date knowledge on how mutation profiles may influence treatment options.

}, keywords = {Adenocarcinoma, Aged, Base Sequence, beta Catenin, Cell Line, Tumor, DNA Mutational Analysis, Female, Frameshift Mutation, Genetic Association Studies, Humans, Kaplan-Meier Estimate, Lung Neoplasms, Male, Middle Aged, Molecular Sequence Data, Mutagenesis, Insertional, Mutation, Missense, Prognosis, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), Receptor, Epidermal Growth Factor, Tumor Suppressor Protein p53}, issn = {1791-2423}, doi = {10.3892/ijo.2012.1396}, author = {Choi, Helen and Kratz, Johannes and Pham, Patrick and Lee, Sharon and Ray, Roshni and Kwon, Yong-Won and Jiang-Hua Mao and Kang, Hio Chung and Jablons, David and Kim, Il-Jin} } @article {189, title = {Evaluating the prognostic significance of FBXW7 expression level in human breast cancer by a meta-analysis of transcriptional profiles.}, journal = {J Cancer Sci Ther}, volume = {4}, year = {2012}, month = {2012 Aug 31}, pages = {299-305}, abstract = {

The tumor suppressor gene FBXW7 is mutated in numerous types of human cancers leading to loss of its function and/or expression. However the clinic significance of FBXW7 alterations remains largely unknown. Here, we carried out a meta-analysis of 10 gene expression microarray studies for a total 1900 patients of breast cancer with clinic information to evaluate the prognostic impact of FBXW7 mRNA expression. The FBXW7 mRNA levels significantly reduced in breast cancer compared to normal tissues. In addition, significant difference in the FBXW7 mRNA levels was found among molecular subtypes (normal-like, luminal A, luminal B, ERBB2 and basal). ERBB2 and basal tumors had significantly lower average FBXW7 mRNA level than normal-like tumors, whereas luminal A and B tumors have the lowest average FBXW7 mRNA level. The patients with higher FBXW7 mRNA level significantly increased disease-free survival, particularly in the group of patients with ER negative and basal subtype tumors. Moreover, higher FBXW7 mRNA level also significantly increased overall survival in the patients with ER negative tumors. But we strikingly found opposite effect of FBXW7 expression on overall survival in different subtypes. The patients with higher FBXW7 mRNA level significantly decreased overall survival in normal-like subtype while the patients with higher FBXW7 mRNA level significantly increased overall survival in ERBB2 and Basal subtype. Taken together, our results suggest that FBXW7 mRNA levels were a prognostic factor for disease-free and overall survival according to ER status and molecular subtypes.

}, issn = {1948-5956}, doi = {10.4172/1948-5956.1000158}, author = {Wei, Guangwei and Wang, Yunshan and Zhang, Pengju and Lu, Jing and Jiang-Hua Mao} } @article {190, title = {The expression of Dishevelled-3 and glutamine metabolism in malignant pleural mesothelioma.}, journal = {J Clin Pathol}, volume = {65}, year = {2012}, month = {2012 Sep}, pages = {855-8}, keywords = {Adaptor Proteins, Signal Transducing, Cell Line, Tumor, Excitatory Amino Acid Transporter 1, Glutamine, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Mesothelioma, Multivariate Analysis, Phosphoproteins, Pleural Neoplasms, Polymerase Chain Reaction, Prognosis, Proportional Hazards Models, Tissue Array Analysis}, issn = {1472-4146}, doi = {10.1136/jclinpath-2011-200628}, author = {Li, Tong and Hou, Sheng-Cai and Jiang-Hua Mao and Wang, Yu-Cheng and Lu, Xiao-Dan and Tan, Jia-Li and You, Bin and Liu, Yu-Ping and Ni, Jian and Au, Alfred and Jablons, David M and Xu, Zhidong and You, Liang} } @article {78, title = {Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e45394}, abstract = {

High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, \<10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGFβ-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p = 0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p\<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer.

}, keywords = {Animals, Breast Neoplasms, Dose-Response Relationship, Radiation, Female, Genetic Predisposition to Disease, Genomic Instability, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Radiation, Ionizing, RNA, Messenger, Survival Analysis, Transcription, Genetic, Tumor Microenvironment}, issn = {1932-6203}, doi = {10.1371/journal.pone.0045394}, author = {A Snijders and Marchetti, Francesco and Bhatnagar, Sandhya and Duru, Nadire and Ju Han and Hu, Zhi and Jiang-Hua Mao and Gray, Joe W and Wyrobek, Andrew J} } @article {183, title = {Gremlin is overexpressed in lung adenocarcinoma and increases cell growth and proliferation in normal lung cells.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e42264}, abstract = {

BACKGROUND: Gremlin, a member of the Dan family of BMP antagonists, is a glycosylated extracellular protein. Previously Gremlin has been shown to play a role in dorsal-ventral patterning, in tissue remodeling, and recently in angiogenesis. Evidence has previously been presented showing both over- and under-expression of Gremlin in different tumor tissues. Here, we sought to quantify expression of Gremlin in cancers of the lung and performed in vitro experiments to check whether Gremlin promotes cell growth and proliferation.

METHODOLOGY/PRINCIPAL FINDINGS: Expression of Gremlin in 161 matched tumor and normal lung cancer specimens is quantified by quantitative real-time PCR and protein level is measured by immunohistochemistry. GREM1 was transfected into lung fibroblast and epithelial cell lines to assess the impact of overexpression of Gremlin in vitro.

RESULTS: Lung adenocarcinoma but not squamous cell carcinoma shows a significant increase in Gremlin expression by mRNA and protein level. Lung fibroblast and epithelial cell lines transfected with GREM1 show significantly increased cell proliferation.

CONCLUSIONS/SIGNIFICANCE: Our data suggest that Gremlin acts in an oncogenic manner in lung adenocarcinoma and could hold promise as a new diagnostic marker or potential therapeutic target in lung AD or general thoracic malignancies.

}, keywords = {Adenocarcinoma, Cell Line, Tumor, Cell Proliferation, Epithelial Cells, Female, Fibroblasts, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Intercellular Signaling Peptides and Proteins, Lung Neoplasms, Male, Neoplasm Proteins, Real-Time Polymerase Chain Reaction, Respiratory Mucosa, RNA, Messenger, RNA, Neoplasm}, issn = {1932-6203}, doi = {10.1371/journal.pone.0042264}, author = {Mulvihill, Michael S and Kwon, Yong-Won and Lee, Sharon and Fang, Li Tai and Choi, Helen and Ray, Roshni and Kang, Hio Chung and Jiang-Hua Mao and Jablons, David and Kim, Il-Jin} } @article {185, title = {Hipk2 cooperates with p53 to suppress γ-ray radiation-induced mouse thymic lymphoma.}, journal = {Oncogene}, volume = {31}, year = {2012}, month = {2012 Mar 1}, pages = {1176-80}, abstract = {

A genome-wide screen for genetic alterations in radiation-induced thymic lymphomas generated from p53+/- and p53-/- mice showed frequent loss of heterozygosity (LOH) on chromosome 6. Fine mapping of these LOH regions revealed three non-overlapping regions, one of which was refined to a 0.2 Mb interval that contained only the gene encoding homeobox-interacting protein kinase 2 (Hipk2). More than 30\% of radiation-induced tumors from both p53+/- and p53-/- mice showed heterozygous loss of one Hipk2 allele. Mice carrying a single inactive allele of Hipk2 in the germline were susceptible to induction of tumors by γ-radiation, but most tumors retained and expressed the wild-type allele, suggesting that Hipk2 is a haploinsufficient tumor suppressor gene for mouse lymphoma development. Heterozygous loss of both Hipk2 and p53 confers strong sensitization to radiation-induced lymphoma. We conclude that Hipk2 is a haploinsufficient lymphoma suppressor gene.

}, keywords = {Animals, Carrier Proteins, Cell Transformation, Neoplastic, Chromosomes, Mammalian, Gamma Rays, Gene Expression Regulation, Neoplastic, Loss of Heterozygosity, Lymphoma, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasms, Radiation-Induced, Protein Binding, Protein-Serine-Threonine Kinases, Thymus Neoplasms, Tumor Suppressor Protein p53}, issn = {1476-5594}, doi = {10.1038/onc.2011.306}, author = {Jiang-Hua Mao and Wu, D and Kim, I-J and Kang, H C and Wei, G and Climent, J and Kumar, A and Pelorosso, F G and DelRosario, R and Huang, E J and Balmain, A} } @article {192, title = {Independent genetic control of early and late stages of chemically induced skin tumors in a cross of a Japanese wild-derived inbred mouse strain, MSM/Ms.}, journal = {Carcinogenesis}, volume = {33}, year = {2012}, month = {2012 Nov}, pages = {2260-8}, abstract = {

MSM/Ms is an inbred mouse strain derived from a Japanese wild mouse, Mus musculus molossinus. In this study, we showed that MSM/Ms mice exhibit dominant resistance when crossed with susceptible FVB/N mice and subjected to the two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA)/ 12-O-tetradecanoylphorbol-13-acetate (TPA). A series of F1 backcross mice were generated by crossing p53(+/+) or p53(+/-) F1 (FVB/N {\texttimes} MSM/Ms) males with FVB/N female mice. These generated 228 backcross animals, approximately half of which were p53(+/-), enabling us to search for p53-dependent skin tumor modifier genes. Highly significant linkage for papilloma multiplicity was found on chromosomes 6 and 7 and suggestive linkage was found on chromosomes 3, 5 and 12. Furthermore, in order to identify stage-dependent linkage loci we classified tumors into three categories (<2mm, 2-6mm and >6mm), and did linkage analysis. The same locus on chromosome 7 showed strong linkage in groups with <2mm or 2-6mm papillomas. No linkage was detected on chromosome 7 to papillomas >6mm, but a different locus on chromosome 4 showed strong linkage both to papillomas >6mm and to carcinomas. This locus, which maps near the Cdkn2a/p19(Arf) gene, was entirely p53-dependent, and was not seen in p53 (+/-) backcross animals. Suggestive linkage conferring susceptibility to carcinoma was also found on chromosome 5. These results clearly suggest distinct loci regulate each stage of tumorigenesis, some of which are p53-dependent.

}, keywords = {9,10-Dimethyl-1,2-benzanthracene, Animals, Carcinogens, Crosses, Genetic, Female, Genetic Linkage, Japan, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Knockout, Papilloma, Skin Neoplasms, Tetradecanoylphorbol Acetate, Tumor Suppressor Protein p53}, issn = {1460-2180}, doi = {10.1093/carcin/bgs250}, author = {Okumura, Kazuhiro and Sato, Miho and Saito, Megumi and Miura, Ikuo and Wakana, Shigeharu and Jiang-Hua Mao and Miyasaka, Yuki and Kominami, Ryo and Wakabayashi, Yuichi} } @article {181, title = {Inhibition of CK2α down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human lung cancer cells.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e38996}, abstract = {

Protein kinase CK2 is frequently elevated in a variety of human cancers. The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance, and its aberrant activation has been indicated in several types of cancer, including lung cancer. In this study, we show that CK2 is positively involved in Hh/Gli signaling in lung cancer cell lines A549 and H1299. First, we found a correlation between CK2α and Gli1 mRNA levels in 100 primary lung cancer tissues. Down-regulation of Gli1 expression and transcriptional activity were demonstrated after the silencing of CK2α in lung cancer cells. In addition, CK2α siRNA down-regulated the expression of Hh target genes. Furthermore, two small-molecule CK2α inhibitors led to a dose-dependent inhibition of Gli1 expression and transcriptional activity in lung cancer cells. Reversely, forced over-expression of CK2α resulted in an increase both in Gli1 expression and transcriptional activity in A549 cells. Finally, the inhibition of Hh/Gli by CK2α siRNA led to a reduction of a cancer stem cell-like side population that shows higher ABCG2 expression level. Thus, we report that the inhibition of CK2α down-regulates Hh/Gli signaling and subsequently reduces stem-like side population in human lung cancer cells.

}, keywords = {ATP-Binding Cassette Transporters, Carcinoma, Non-Small-Cell Lung, Casein Kinase II, Cell Count, Cell Line, Tumor, Down-Regulation, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Gene Silencing, Humans, Lung Neoplasms, Neoplasm Proteins, Neoplastic Stem Cells, Protein Kinase Inhibitors, Proteolysis, Side-Population Cells, Signal Transduction, Small Molecule Libraries, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Up-Regulation}, issn = {1932-6203}, doi = {10.1371/journal.pone.0038996}, author = {Zhang, Shulin and Wang, Yucheng and Jiang-Hua Mao and Hsieh, David and Kim, Il-Jin and Hu, Li-Min and Xu, Zhidong and Long, Hao and Jablons, David M and You, Liang} } @article {193, title = {Low-dose ionizing radiation-induced blood plasma metabolic response in a diverse genetic mouse population.}, journal = {Radiat Res}, volume = {178}, year = {2012}, month = {2012 Dec}, pages = {551-5}, abstract = {

Understanding the biological effects and biochemical mechanisms of low-dose ionizing radiation (LDIR) is important for setting exposure limits for the safe use of nuclear power and medical diagnostic procedures. Although several studies have highlighted the effects of ionizing radiation on metabolism, most studies have focused on uniform genetic mouse populations. Here, we report the metabolic response to LDIR (10 cGy X ray) on a genetically diverse mouse population (142 mice) generated from a cross of radiation-sensitive (BALB/c) and radiation-resistant (SPRET/EiJ) parental strains. GC-TOF profiling of plasma metabolites was used to compare exposed vs. sham animals. From this, 16 metabolites were significantly altered in the LDIR treated vs. sham group. Use of two significantly altered metabolites, thymine and 2-monostearin, was found to effectively segregate the two treatments. Multivariate statistical analysis was used to identify genetic polymorphisms correlated with metabolite abundance (e.g., amino acids, fatty acids, nucleotides and TCA cycle intermediates). Genetic analysis of metabolic phenotypes showed suggestive linkages for fatty acid and amino acid metabolism. However, metabolite abundance was found to be a function of low-dose ionizing radiation exposure, and not of the underlying genetic variation.

}, keywords = {Animals, Blood, Crosses, Genetic, Dose-Response Relationship, Radiation, Female, Genetic Variation, Male, Metabolome, Mice, Mice, Inbred BALB C, Species Specificity, Transcriptome}, issn = {1938-5404}, doi = {10.1667/RR2990.1}, author = {Lee, Do Yup and Bowen, Benjamin P and Nguyen, David H and Parsa, Sara and Huang, Yurong and Jiang-Hua Mao and Northen, Trent R} } @article {182, title = {Multiple novel alternative splicing forms of FBXW7α have a translational modulatory function and show specific alteration in human cancer.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e49453}, abstract = {

FBXW7 acts as a tumor suppressor through ubiquitination and degradation of multiple oncoproteins. Loss of FBXW7 expression, which could be partially attributed by the genomic deletion or mutation of FBXW7 locus, is frequently observed in various human cancers. However, the mechanisms regulating FBXW7 expression still remain poorly understood. Here we examined the 5{\textquoteright} region of FBXW7 gene to investigate the regulation of FBXW7 expression. We identified seven alternative splicing (AS) 5{\textquoteright}-UTR forms of FBXW7α that are composed of multiple novel non-coding exons. A significant difference in translational efficiency among these 5{\textquoteright}-UTRs variants was observed by in vivo Luciferase reporter assay and Western blot. Furthermore, we found that the mRNA level of the AS form with high translational efficiency was specifically reduced in more than 80\% of breast cancer cell lines and in more than 50\% of human primary cancers from various tissues. In addition, we also identified mutations of FBXW7 in prostate cancers (5.6\%), kidney cancers (16.7\%), and bladder cancers (18.8\%). Our results suggest that in addition to mutation, differential expression of FBXW7α AS forms with different translational properties may serve as a novel mechanism for inactivation of FBXW7 in human cancer.

}, keywords = {Alternative Splicing, Analysis of Variance, Blotting, Western, Cell Cycle Proteins, Computational Biology, DNA Mutational Analysis, Exons, F-Box Proteins, Gene Components, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Luciferases, Neoplasms, Protein Biosynthesis, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Ubiquitin-Protein Ligases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0049453}, author = {Liu, Yueyong and Ren, Shancheng and Castellanos-Mart{\'\i}n, Andr{\'e}s and Perez-Losada, Jesus and Kwon, Yong-Won and Huang, Yurong and Wang, Zeran and Abad, Mar and Cruz-Hernandez, Juan J and Rodriguez, Cesar A and Sun, Yinghao and Jiang-Hua Mao} } @article {191, title = {Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer.}, journal = {J Mol Med (Berl)}, volume = {90}, year = {2012}, month = {2012 Oct}, pages = {1121-32}, abstract = {

Thalidomide is experimentally used to treat various human cancers; however, clinical responses to thalidomide are sporadic. Here we demonstrate that CUL4A plays an oncogenic role in prostate cancer development and prostate cancer cells with higher level of CUL4A are particularly sensitive to thalidomide treatment. We show that CUL4A is frequently overexpressed in human primary prostate cancer and cell lines. Notably, subjects with tumors that highly expressed CUL4A had poor overall survival. CUL4A downregulation inhibited cell proliferation and induced apoptosis in vitro and in vivo, whereas CUL4A overexpression transformed human normal prostate epithelial cells and promoted invasion, which was attenuated by the extracellular signal-regulated kinase (ERK) inhibitor. We further show that the sensitivity to thalidomide is positively correlated with CUL4A expression in a panel of prostate cell lines. Ectopic CUL4A expression greatly enhanced sensitivity to thalidomide, while its downregulation conferred resistance to this drug. Mechanistically, thalidomide decreased CUL4A in a time- and dose-dependent manner, consequently leading to inaction of ERK pathway. Finally, we show that cereblon level is correlated with CUL4A expression and downregulated in thalidomide-resistant prostate cancer cell. Our results offer the first evidence that CUL4A is a potential therapeutic target for prostate cancer and may serve as a biomarker for assessing prognosis of human prostate cancer and response to thalidomide treatment.

}, keywords = {Angiogenesis Inhibitors, Animals, Apoptosis, Cell Line, Tumor, Cell Survival, Cullin Proteins, Gene Expression, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Kaplan-Meier Estimate, Male, MAP Kinase Signaling System, Mice, Mice, Nude, Neoplasm Transplantation, Peptide Hydrolases, Prostatic Neoplasms, RNA Interference, Thalidomide, Tissue Array Analysis, Tumor Burden}, issn = {1432-1440}, doi = {10.1007/s00109-012-0885-0}, author = {Ren, Shancheng and Xu, Chuanliang and Cui, Zilian and Yu, Yongwei and Xu, Weidong and Wang, Fubo and Lu, Ji and Wei, Min and Lu, Xin and Gao, Xu and Liang, You and Jiang-Hua Mao and Sun, Yinghao} } @article {188, title = {Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development.}, journal = {Mol Cancer Res}, volume = {10}, year = {2012}, month = {2012 Jun}, pages = {834-44}, abstract = {

The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3β. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3β-binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7-dependent degradation of Aurora-A through the AKT/GSK3β pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7(+/-)Pten(+/-) mice as compared with either Fbxw7(+/-) or Pten(+/-) mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level.

}, keywords = {Animals, Aurora Kinase A, Aurora Kinases, Binding Sites, Blotting, Western, Cell Line, F-Box Proteins, Female, Gamma Rays, Glycogen Synthase Kinase 3, HCT116 Cells, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Neoplasms, Radiation-Induced, NIH 3T3 Cells, Protein Binding, Protein-Serine-Threonine Kinases, PTEN Phosphohydrolase, Time Factors, Ubiquitin, Ubiquitin-Protein Ligases}, issn = {1557-3125}, doi = {10.1158/1541-7786.MCR-12-0025}, author = {Kwon, Yong-Won and Kim, Il-Jin and Wu, Di and Lu, Jing and Stock, William A and Liu, Yueyong and Huang, Yurong and Kang, Hio Chung and DelRosario, Reyno and Jen, Kuang-Yu and Perez-Losada, Jesus and Wei, Guangwei and Balmain, Allan and Jiang-Hua Mao} } @article {186, title = {RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings.}, journal = {Cell Res}, volume = {22}, year = {2012}, month = {2012 May}, pages = {806-21}, abstract = {

There are remarkable disparities among patients of different races with prostate cancer; however, the mechanism underlying this difference remains unclear. Here, we present a comprehensive landscape of the transcriptome profiles of 14 primary prostate cancers and their paired normal counterparts from the Chinese population using RNA-seq, revealing tremendous diversity across prostate cancer transcriptomes with respect to gene fusions, long noncoding RNAs (long ncRNA), alternative splicing and somatic mutations. Three of the 14 tumors (21.4\%) harbored a TMPRSS2-ERG fusion, and the low prevalence of this fusion in Chinese patients was further confirmed in an additional tumor set (10/54=18.5\%). Notably, two novel gene fusions, CTAGE5-KHDRBS3 (20/54=37\%) and USP9Y-TTTY15 (19/54=35.2\%), occurred frequently in our patient cohort. Further systematic transcriptional profiling identified numerous long ncRNAs that were differentially expressed in the tumors. An analysis of the correlation between expression of long ncRNA and genes suggested that long ncRNAs may have functions beyond transcriptional regulation. This study yielded new insights into the pathogenesis of prostate cancer in the Chinese population.

}, keywords = {Alternative Splicing, Antigens, Neoplasm, Base Sequence, China, Chromosomes, Human, Pair 21, Cohort Studies, Gene Fusion, Genome, Human, Humans, Male, Mutation, Neoplasm Proteins, Prostatic Neoplasms, PTEN Phosphohydrolase, Recurrence, RNA, Untranslated, RNA-Binding Proteins, Sequence Analysis, RNA, Serine Endopeptidases, Trans-Activators, Transcriptome, Ubiquitin Thiolesterase}, issn = {1748-7838}, doi = {10.1038/cr.2012.30}, author = {Ren, Shancheng and Peng, Zhiyu and Jiang-Hua Mao and Yu, Yongwei and Yin, Changjun and Gao, Xin and Cui, Zilian and Zhang, Jibin and Yi, Kang and Xu, Weidong and Chen, Chao and Wang, Fubo and Guo, Xinwu and Lu, Ji and Yang, Jun and Wei, Min and Tian, Zhijian and Guan, Yinghui and Tang, Liang and Xu, Chuanliang and Wang, Linhui and Gao, Xu and Tian, Wei and Wang, Jian and Yang, Huanming and Wang, Jun and Sun, Yinghao} } @article {184, title = {Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas.}, journal = {Blood}, volume = {119}, year = {2012}, month = {2012 Jan 19}, pages = {805-9}, abstract = {

T-cell acute lymphoblastic lymphomas commonly demonstrate activating Notch1 mutations as well as mutations or deletions in Fbxw7. However, because Fbxw7 targets Notch1 for degradation, genetic alterations in these genes are expected to be mutually exclusive events in lymphomagenesis. Previously, by using a radiation-induced Tp53-deficient mouse model for T-cell acute lymphoblastic lymphoma, we reported that loss of heterozygosity at the Fbxw7 locus occurs frequently in a Tp53-dependent manner. In the current study, we show that these thymic lymphomas also commonly exhibit activating Notch1 mutations in the proline-glutamic acid-serine-threonine (PEST) domain. Moreover, concurrent activating Notch1 PEST domain mutations and single-copy deletions at the Fbxw7 locus occur with high frequency in the same individual tumors, indicating that these changes are not mutually exclusive events. We further demonstrate that although Notch1 PEST domain mutations are independent of Tp53 status, they are completely abolished in mice with germline Fbxw7 haploinsufficiency. Therefore, Notch1 PEST domain mutations only occur when Fbxw7 expression levels are intact. These data suggest a temporal sequence of mutational events involving these important cancer-related genes, with Notch1 PEST domain mutations occurring first, followed by Fbxw7 deletion, and eventually by complete loss of Tp53.

}, keywords = {Animals, Disease Models, Animal, F-Box Proteins, Female, Loss of Heterozygosity, Male, Mice, Mice, Knockout, Mutation, Neoplasms, Radiation-Induced, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein Structure, Tertiary, Real-Time Polymerase Chain Reaction, Receptor, Notch1, RNA, Messenger, Thymus Neoplasms, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases}, issn = {1528-0020}, doi = {10.1182/blood-2011-01-327619}, author = {Jen, Kuang-Yu and Song, Ihn Young and Banta, Karl Luke and Wu, Di and Jiang-Hua Mao and Balmain, Allan} } @article {176, title = {Cancer evolution and individual susceptibility.}, journal = {Integr Biol (Camb)}, volume = {3}, year = {2011}, month = {2011 Apr}, pages = {316-28}, abstract = {

Cancer susceptibility is due to interactions between inherited genetic factors and exposure to environmental carcinogens. The genetic component is constituted mainly by weakly acting low-penetrance genetic variants that interact among themselves, as well as with the environment. These low susceptibility genes can be categorized into two main groups: one includes those that control intrinsic tumor cell activities (i.e. apoptosis, proliferation or DNA repair), and the other contains those that modulate the function of extrinsic tumor cell compartments (i.e. stroma, angiogenesis, or endocrine and immune systems). Genome-Wide Association Studies (GWAS) of human populations have identified numerous genetic loci linked with cancer risk and behavior, but nevertheless the major component of cancer heritability remains to be explained. One reason may be that GWAS cannot readily capture gene-gene or gene-environment interactions. Mouse model approaches offer an alternative or complementary strategy, because of our ability to control both the genetic and environmental components of risk. Recently developed genetic tools, including high-throughput technologies such as SNP, CGH and gene expression microarrays, have led to more powerful strategies for refining quantitative trait loci (QTL) and identifying the critical genes. In particular, the cross-species approaches will help to refine locations of QTLs, and reveal their genetic and environmental interactions. The identification of human tumor susceptibility genes and discovery of their roles in carcinogenesis will ultimately be important for the development of methods for prediction of risk, diagnosis, prevention and therapy for human cancers.

}, keywords = {Animals, Disease Susceptibility, Environmental Exposure, Genome-Wide Association Study, Humans, Neoplasms, Quantitative Trait Loci}, issn = {1757-9708}, doi = {10.1039/c0ib00094a}, author = {Perez-Losada, Jesus and Castellanos-Mart{\'\i}n, Andr{\'e}s and Jiang-Hua Mao} } @article {173, title = {Cul4A is an oncogene in malignant pleural mesothelioma.}, journal = {J Cell Mol Med}, volume = {15}, year = {2011}, month = {2011 Feb}, pages = {350-8}, abstract = {

Cullin 4A (Cul4A) is important in cell survival, development, growth and the cell cycle, but its role in mesothelioma has not been studied. For the first time, we identified amplification of the Cul4A gene in four of five mesothelioma cell lines. Consistent with increased Cul4A gene copy number, we found that Cul4A protein was overexpressed in mesothelioma cells as well. Cul4A protein was also overexpressed in 64\% of primary malignant pleural mesothelioma (MPM) tumours. Furthermore, knockdown of Cul4A with shRNA in mesothelioma cells resulted in up-regulation of p21 and p27 tumour suppressor proteins in a p53-independent manner in H290, H28 and MS-1 mesothelioma cell lines. Knockdown of Cul4A also resulted in G0/G1 cell cycle arrest and decreased colony formation in H290, H28 and MS-1 mesothelioma cell lines. Moreover, G0/G1 cell cycle arrest was partially reversed by siRNA down-regulation of p21 and/or p27 in Cul4A knockdown H290 cell line. In the contrary, overexpression of Cul4A resulted in down-regulation of p21 and p27 proteins and increased colony formation in H28 mesothelioma cell line. Both p21 and p27 showed faster degradation rates in Cul4A overexpressed H28 cell line and slower degradation rates in Cul4A knockdown H28 cell line. Our study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma. Thus, Cul4A may be a potential therapeutic target for MPM.

}, keywords = {Cell Cycle, Cell Line, Tumor, Cullin Proteins, Humans, Mesothelioma, Oncogenes, Pleural Neoplasms, Proliferating Cell Nuclear Antigen, rho GTP-Binding Proteins, RNA Interference, RNA, Small Interfering, Signal Transduction}, issn = {1582-4934}, doi = {10.1111/j.1582-4934.2009.00971.x}, author = {Hung, Ming-Szu and Jiang-Hua Mao and Xu, Zhidong and Yang, Cheng-Ta and Yu, Jau-Song and Harvard, Chansonette and Lin, Yu-Ching and Bravo, Dawn Therese and Jablons, David M and You, Liang} } @article {178, title = {Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity.}, journal = {Genes Dev}, volume = {25}, year = {2011}, month = {2011 Jul 1}, pages = {1426-38}, abstract = {

Cell cycle regulation in hematopoietic stem cells (HSCs) is tightly controlled during homeostasis and in response to extrinsic stress. p53, a well-known tumor suppressor and transducer of diverse stress signals, has been implicated in maintaining HSC quiescence and self-renewal. However, the mechanisms that control its activity in HSCs, and how p53 activity contributes to HSC cell cycle control, are poorly understood. Here, we use a genetically engineered mouse to show that p53 C-terminal modification is critical for controlling HSC abundance during homeostasis and HSC and progenitor proliferation after irradiation. Preventing p53 C-terminal modification renders mice exquisitely radiosensitive due to defects in HSC/progenitor proliferation, a critical determinant for restoring hematopoiesis after irradiation. We show that fine-tuning the expression levels of the cyclin-dependent kinase inhibitor p21, a p53 target gene, contributes significantly to p53-mediated effects on the hematopoietic system. These results have implications for understanding cell competition in response to stresses involved in stem cell transplantation, recovery from adverse hematologic effects of DNA-damaging cancer therapies, and development of radioprotection strategies.

}, keywords = {Animals, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Female, Gamma Rays, Gene Dosage, Gene Expression Regulation, Gene Knock-In Techniques, Hematopoietic Stem Cells, Homeostasis, Longevity, Male, Mice, Mice, Inbred C57BL, Mutation, Proto-Oncogene Proteins c-mdm2, Radiation Tolerance, Tumor Suppressor Protein p53}, issn = {1549-5477}, doi = {10.1101/gad.2024411}, author = {Wang, Yunyuan V and Leblanc, Mathias and Fox, Norma and Jiang-Hua Mao and Tinkum, Kelsey L and Krummel, Kurt and Engle, Dannielle and Piwnica-Worms, David and Piwnica-Worms, Helen and Balmain, Allan and Kaushansky, Kenneth and Wahl, Geoffrey M} } @article {175, title = {Gene transcriptional networks integrate microenvironmental signals in human breast cancer.}, journal = {Integr Biol (Camb)}, volume = {3}, year = {2011}, month = {2011 Apr}, pages = {368-74}, abstract = {

A significant amount of evidence shows that microenvironmental signals generated from extracellular matrix (ECM) molecules, soluble factors, and cell-cell adhesion complexes cooperate at the extra- and intracellular level. This synergetic action of microenvironmental cues is crucial for normal mammary gland development and breast malignancy. To explore how the microenvironmental genes coordinate in human breast cancer at the genome level, we have performed gene co-expression network analysis in three independent microarray datasets and identified two microenvironment networks in human breast cancer tissues. Network I represents crosstalk and cooperation of ECM microenvironment and soluble factors during breast malignancy. The correlated expression of cytokines, chemokines, and cell adhesion proteins in Network II implicates the coordinated action of these molecules in modulating the immune response in breast cancer tissues. These results suggest that microenvironmental cues are integrated with gene transcriptional networks to promote breast cancer development.

}, keywords = {Breast Neoplasms, Cadherins, Cytokines, Extracellular Matrix, Extracellular Matrix Proteins, Female, Gene Expression Profiling, Gene Regulatory Networks, Humans, Integrins, Intercellular Signaling Peptides and Proteins, Mammary Glands, Human, Oligonucleotide Array Sequence Analysis, Receptor, Platelet-Derived Growth Factor beta, Receptors, Cytokine, Transforming Growth Factor beta, Tumor Microenvironment}, issn = {1757-9708}, doi = {10.1039/c0ib00087f}, author = {Xu, Ren and Jiang-Hua Mao} } @article {179, title = {Progressive genomic instability in the FVB/Kras(LA2) mouse model of lung cancer.}, journal = {Mol Cancer Res}, volume = {9}, year = {2011}, month = {2011 Oct}, pages = {1339-45}, abstract = {

Alterations in DNA copy number contribute to the development and progression of cancers and are common in epithelial tumors. We have used array Comparative Genomic Hybridization (aCGH) to visualize DNA copy number alterations across the genomes of lung tumors in the Kras(LA2) model of lung cancer. Copy number gain involving the Kras locus, as focal amplification or whole chromosome gain, is the most common alteration in these tumors and with a prevalence that increased significantly with increasing tumor size. Furthermore, Kras amplification was the only major genomic event among the smallest lung tumors, suggesting that this alteration occurs early during the development of mutant Kras-driven lung cancers. Recurring gains and deletions of other chromosomes occur progressively more frequently among larger tumors. These results are in contrast to a previous aCGH analysis of lung tumors from Kras(LA2) mice on a mixed genetic background, in which relatively few DNA copy number alterations were observed regardless of tumor size. Our model features the Kras(LA2) allele on the inbred FVB/N mouse strain, and in this genetic background, there is a highly statistically significant increase in level of genomic instability with increasing tumor size. These data suggest that recurring DNA copy alterations are important for tumor progression in the Kras(LA2) model of lung cancer and that the requirement for these alterations may be dependent on the genetic background of the mouse strain.

}, keywords = {Animals, Cell Line, Tumor, Chromosome Aberrations, Disease Models, Animal, Disease Progression, DNA Copy Number Variations, DNA, Neoplasm, Gene Dosage, Gene Expression Regulation, Neoplastic, Genes, ras, Genomic Instability, Lung Neoplasms, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins p21(ras)}, issn = {1557-3125}, doi = {10.1158/1541-7786.MCR-11-0219}, author = {To, Minh D and Quigley, David A and Jiang-Hua Mao and Del Rosario, Reyno and Hsu, Jeff and Hodgson, Graeme and Jacks, Tyler and Balmain, Allan} } @article {177, title = {Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type.}, journal = {Cancer Cell}, volume = {19}, year = {2011}, month = {2011 May 17}, pages = {640-51}, abstract = {

Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from tumors arising in nonirradiated hosts. Molecular and genetic approaches show that TGFβ mediated tumor acceleration. Tumor molecular signatures implicated TGFβ, and genetically reducing TGFβ abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFβ independent and linked to mammary stem cell activity. Thus, the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms.

}, keywords = {Animals, Breast Neoplasms, Cell Transformation, Neoplastic, Dose-Response Relationship, Radiation, Epithelial Cells, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Mammary Glands, Animal, Mice, Mice, Inbred BALB C, Mice, Knockout, Neoplasms, Radiation-Induced, Radiation Chimera, Reaction Time, Receptors, Estrogen, Time Factors, Transforming Growth Factor beta1, Tumor Burden, Tumor Microenvironment, Tumor Suppressor Protein p53, Whole-Body Irradiation}, issn = {1878-3686}, doi = {10.1016/j.ccr.2011.03.011}, author = {Nguyen, David H and Oketch-Rabah, Hellen A and Illa-Bochaca, Irineu and Geyer, Felipe C and Reis-Filho, Jorge S and Jiang-Hua Mao and Ravani, Shraddha A and Zavadil, Jiri and Borowsky, Alexander D and Jerry, D Joseph and Dunphy, Karen A and Seo, Jae Hong and Haslam, Sandra and Medina, Daniel and Barcellos-Hoff, Mary Helen} } @article {174, title = {Transgenic mice for cre-inducible overexpression of the Cul4A gene.}, journal = {Genesis}, volume = {49}, year = {2011}, month = {2011 Mar}, pages = {134-41}, abstract = {

The Cullin 4A(Cul4A) gene is important in cell survival, development, growth, and cell cycle control and is amplified in breast and hepatocellular cancers. Recently, we reported that Cul4A plays an oncogenic role in the pathogenesis of mesothelioma. An important strategy for studying Cul4A in different tissues is targeted overexpression of this gene in vivo. Studies of Cul4A in mice have been restricted to the loss-of-function studies using Cul4A knockout mice; gain-of-function studies of Cul4A using transgenic mice have not been reported. We, therefore, generated a gain-of-function transgenic mouse model that overexpresses Cul4A in a Cre-dependent manner. Before Cre recombination, these mice express LacZ during development in most adult tissues. After Cre-mediated excision of the LacZ reporter, the transfected Cul4A gene is expressed along with a C-terminal Myc-tag in different tissues. In this study, Cre-excision was induced in mouse lungs by inhalation of an adenovirus vector encoding Cre recombinase. This mouse model provides a valuable resource for investigating the significance of Cul4A overexpression in various tissues.

}, keywords = {Adenoviridae, Animals, Cullin Proteins, Gene Expression Regulation, Genes, Reporter, Genetic Vectors, Integrases, Lac Operon, Mice, Mice, Knockout, Mice, Transgenic, Models, Animal, Promoter Regions, Genetic, Recombination, Genetic, Transgenes}, issn = {1526-968X}, doi = {10.1002/dvg.20708}, author = {Li, Tong and Hung, Ming-Szu and Wang, Yucheng and Jiang-Hua Mao and Tan, Jia-Li and Jahan, Kenneth and Roos, Hannah and Xu, Zhidong and Jablons, David M and You, Liang} } @article {171, title = {Deletion of the PER3 gene on chromosome 1p36 in recurrent ER-positive breast cancer.}, journal = {J Clin Oncol}, volume = {28}, year = {2010}, month = {2010 Aug 10}, pages = {3770-8}, abstract = {

PURPOSE: To investigate the role of the PER3 circadian rhythm gene, located within the commonly deleted region of chromosome 1p36, in human breast cancer development.

PATIENTS AND METHODS: The frequency of genetic alterations at 1p36 and PER3 gene copy number status were analyzed in 180 lymph node-negative breast cancers from patients who had received treatment with chemotherapy and/or tamoxifen. The expression levels of PER3 were also analyzed using published microarray profiles from > 400 breast cancer samples. Finally, the effect of loss of Per3 on tumor susceptibility was tested using two mouse models of breast cancer.

RESULTS: Deletion of PER3 is directly related to tumor recurrence in patients with estrogen receptor (ER) - positive breast cancers treated with tamoxifen. Low expression of PER3 mRNA is associated with poor prognosis, particularly in a subset of tumors that are ER positive, and either luminal A or ERBB2-positive tumors. Mice deficient in Per3 showed increased susceptibility to breast cancer induced by carcinogen treatment or by overexpression of Erbb2.

CONCLUSION: Disruption of PER3 function may serve as an indicator of probability of tumor recurrence in patients with ER-positive tumors. Further investigations of this pathway may reveal links between deregulation of sleep homeostasis and breast tumorigenesis.

}, keywords = {Animals, Breast Neoplasms, Chromosomes, Human, Pair 1, Disease Models, Animal, Female, Gene Dosage, Gene Expression, Genetic Predisposition to Disease, Humans, Mice, Neoplasm Recurrence, Local, Period Circadian Proteins, Prognosis, Receptors, Estrogen, Sequence Deletion, Survival Analysis}, issn = {1527-7755}, doi = {10.1200/JCO.2009.27.0215}, author = {Climent, Joan and Perez-Losada, Jesus and Quigley, David A and Kim, Il-Jin and DelRosario, Reyno and Jen, Kuang-Yu and Bosch, Ana and Lluch, Ana and Jiang-Hua Mao and Balmain, Allan} } @article {167, title = {The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer.}, journal = {Breast Cancer Res}, volume = {12}, year = {2010}, month = {2010}, pages = {R18}, abstract = {

INTRODUCTION: HJURP (Holliday Junction Recognition Protein) is a newly discovered gene reported to function at centromeres and to interact with CENPA. However its role in tumor development remains largely unknown. The goal of this study was to investigate the clinical significance of HJURP in breast cancer and its correlation with radiotherapeutic outcome.

METHODS: We measured HJURP expression level in human breast cancer cell lines and primary breast cancers by Western blot and/or by Affymetrix Microarray; and determined its associations with clinical variables using standard statistical methods. Validation was performed with the use of published microarray data. We assessed cell growth and apoptosis of breast cancer cells after radiation using high-content image analysis.

RESULTS: HJURP was expressed at higher level in breast cancer than in normal breast tissue. HJURP mRNA levels were significantly associated with estrogen receptor (ER), progesterone receptor (PR), Scarff-Bloom-Richardson (SBR) grade, age and Ki67 proliferation indices, but not with pathologic stage, ERBB2, tumor size, or lymph node status. Higher HJURP mRNA levels significantly decreased disease-free and overall survival. HJURP mRNA levels predicted the prognosis better than Ki67 proliferation indices. In a multivariate Cox proportional-hazard regression, including clinical variables as covariates, HJURP mRNA levels remained an independent prognostic factor for disease-free and overall survival. In addition HJURP mRNA levels were an independent prognostic factor over molecular subtypes (normal like, luminal, Erbb2 and basal). Poor clinical outcomes among patients with high HJURP expression were validated in five additional breast cancer cohorts. Furthermore, the patients with high HJURP levels were much more sensitive to radiotherapy. In vitro studies in breast cancer cell lines showed that cells with high HJURP levels were more sensitive to radiation treatment and had a higher rate of apoptosis than those with low levels. Knock down of HJURP in human breast cancer cells using shRNA reduced the sensitivity to radiation treatment. HJURP mRNA levels were significantly correlated with CENPA mRNA levels.

CONCLUSIONS: HJURP mRNA level is a prognostic factor for disease-free and overall survival in patients with breast cancer and is a predictive biomarker for sensitivity to radiotherapy.

}, keywords = {Biomarkers, Tumor, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Disease-Free Survival, DNA-Binding Proteins, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Oligonucleotide Array Sequence Analysis, Predictive Value of Tests, Prognosis, RNA Interference, RNA, Messenger}, issn = {1465-542X}, doi = {10.1186/bcr2487}, author = {Hu, Zhi and Huang, Ge and Sadanandam, Anguraj and Gu, Shenda and Lenburg, Marc E and Pai, Melody and Bayani, Nora and Blakely, Eleanor A and Gray, Joe W and Jiang-Hua Mao} } @article {170, title = {Functional polymorphism of the CK2alpha intronless gene plays oncogenic roles in lung cancer.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010}, pages = {e11418}, abstract = {

Protein kinase CK2 is frequently up-regulated in human cancers, although the mechanism of CK2 activation in cancer remains unknown. In this study, we investigated the role of the CK2alpha intronless gene (CSNK2A1P, a presumed CK2alpha pseudogene) in the pathogenesis of human cancers. We found evidence of amplification and over-expression of the CSNK2A1P gene in non-small cell lung cancer and leukemia cell lines and 25\% of the lung cancer tissues studied. The mRNA expression levels correlated with the copy numbers of the CSNK2A1P gene. We also identified a novel polymorphic variant (398T/C, I133T) of the CSNK2A1P gene and showed that the 398T allele is selectively amplified over the 398C allele in 101 non-small cell lung cancer tissue samples compared to those in 48 normal controls (p = 0.013<0.05). We show for the first time CSNK2A1P protein expression in transfected human embryonic kidney 293T and mouse embryonic fibroblast NIH-3T3 cell lines. Both alleles are transforming in these cell lines, and the 398T allele appears to be more transforming than the 398C allele. Moreover, the 398T allele degrades PML tumor suppressor protein more efficiently than the 398C allele and shows a relatively stronger binding to PML. Knockdown of the CSNK2A1P gene expression with specific siRNA increased the PML protein level in lung cancer cells. We report, for the first time, that the CSNK2A1P gene is a functional proto-oncogene in human cancers and its functional polymorphism appears to degrade PML differentially in cancer cells. These results are consistent with an important role for the 398T allele of the CSNK2A1P in human lung cancer susceptibility.

}, keywords = {Animals, Blotting, Western, Casein Kinase II, Cell Line, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Immunoprecipitation, In Situ Hybridization, Fluorescence, In Vitro Techniques, Lung Neoplasms, Mice, NIH 3T3 Cells, Nuclear Proteins, Polymorphism, Genetic, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Sequence Analysis, DNA, Transcription Factors, Tumor Suppressor Proteins}, issn = {1932-6203}, doi = {10.1371/journal.pone.0011418}, author = {Hung, Ming-Szu and Lin, Yu-Ching and Jiang-Hua Mao and Kim, Il-Jin and Xu, Zhidong and Yang, Cheng-Ta and Jablons, David M and You, Liang} } @article {168, title = {An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis.}, journal = {Oncogene}, volume = {29}, year = {2010}, month = {2010 May 6}, pages = {2659-71}, abstract = {

There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.

}, keywords = {Acetylation, Animals, Binding Sites, Cell Division, Chromosome Fragile Sites, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, G2 Phase, Histone Deacetylase 1, Humans, Mice, Neoplasms, Radiation-Induced, NIH 3T3 Cells, Tumor Suppressor Proteins, Ubiquitination}, issn = {1476-5594}, doi = {10.1038/onc.2010.19}, author = {Li, Z and Zhang, Q and Jiang-Hua Mao and Weise, A and Mrasek, K and Fan, X and Zhang, X and Liehr, T and Lu, K H and Balmain, A and Cai, W-W} } @article {172, title = {Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis.}, journal = {Proc Natl Acad Sci U S A}, volume = {107}, year = {2010}, month = {2010 Oct 5}, pages = {17268-73}, abstract = {

Cancer is a disease subject to both genetic and environmental influences. In this study, we used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to identify a genetic locus that influences tumor progression to an invasive growth state. RT2 mice inbred into the C57BL/6 (B6) background develop both noninvasive pancreatic neuroendocrine tumors (PNET) and invasive carcinomas with varying degrees of aggressiveness. In contrast, RT2 mice inbred into the C3HeB/Fe (C3H) background are comparatively resistant to the development of invasive tumors, as are RT2 C3HB6(F1) hybrid mice. Using linkage analysis, we identified a 13-Mb locus on mouse chromosome 17 with significant linkage to the development of highly invasive PNETs. A gene residing in this locus, the anaplastic lymphoma kinase (Alk), was expressed at significantly lower levels in PNETs from invasion-resistant C3H mice compared with invasion-susceptible B6 mice, and pharmacological inhibition of Alk led to reduced tumor invasiveness in RT2 B6 mice. Collectively, our results demonstrate that tumor invasion is subject to polymorphic genetic control and identify Alk as a genetic modifier of invasive tumor growth.

}, keywords = {Adenoma, Islet Cell, Animals, Cell Transformation, Neoplastic, Chromosomes, Mammalian, Genetic Linkage, Genetic Loci, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Pancreatic Neoplasms, Polymorphism, Genetic, Protein-Tyrosine Kinases, Pyrimidines, Receptor Protein-Tyrosine Kinases}, issn = {1091-6490}, doi = {10.1073/pnas.1012705107}, author = {Chun, Matthew G H and Jiang-Hua Mao and Chiu, Christopher W and Balmain, Allan and Hanahan, Douglas} } @article {169, title = {Presenilin modulates EGFR signaling and cell transformation by regulating the ubiquitin ligase Fbw7.}, journal = {Oncogene}, volume = {29}, year = {2010}, month = {2010 May 20}, pages = {2950-61}, abstract = {

The epidermal growth factor receptor (EGFR) and Notch signaling pathways have antagonistic roles during epidermal differentiation and carcinogenesis. The molecular mechanisms regulating the crosstalk between EGFR and Notch during epidermal transformation are largely unknown. We found enhanced EGFR-dependent signaling, proliferation and oncogenic transformation caused by loss of presenilins (PS), the catalytic components of gamma-secretase that generates the Notch1 intracellular domain (NICD). The underlying mechanism for abnormal EGFR signaling in PS-deficient cells involves gamma-secretase-independent transcriptional upregulation of the E3 ubiquitin ligase Fbw7. Fbw7alpha, which targets NICD for degradation, regulates positively EGFR by affecting a proteasome-dependent ubiquitination step essential for constitutive degradation and stability of EGFR. To investigate the pathological relevance of this findings in vivo, we generated a novel epidermal conditional PS-deficient (ePS cDKO) mouse by deleting both PS in keratinocytes of the basal layer of the epidermis. The ePS cDKO mice develop epidermal hyperplasia associated with enhanced expression of both EGFR and Fbw7 and reduced NICD levels in keratinocytes. These findings establish a novel role for PS on epidermal growth and transformation by reciprocally regulating the EGFR and Notch signaling pathways through Fbw7.

}, keywords = {Animals, Blotting, Western, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Embryo, Mammalian, F-Box Proteins, Fibroblasts, Fluorescent Antibody Technique, Gene Expression Regulation, Hyperplasia, Immunoenzyme Techniques, Integrases, Keratinocytes, Mice, Mice, Knockout, Presenilins, Receptor, Epidermal Growth Factor, Signal Transduction, Ubiquitin, Ubiquitin-Protein Ligases}, issn = {1476-5594}, doi = {10.1038/onc.2010.57}, author = {Rocher-Ros, V and Marco, S and Jiang-Hua Mao and Gines, S and Metzger, D and Chambon, P and Balmain, A and Saura, C A} } @article {165, title = {Genetic architecture of mouse skin inflammation and tumour susceptibility.}, journal = {Nature}, volume = {458}, year = {2009}, month = {2009 Mar 26}, pages = {505-8}, abstract = {

Germline polymorphisms in model organisms and humans influence susceptibility to complex trait diseases such as inflammation and cancer. Mice of the Mus spretus species are resistant to tumour development, and crosses between M. spretus and susceptible Mus musculus strains have been used to map locations of genetic variants that contribute to skin cancer susceptibility. We have integrated germline polymorphisms with gene expression in normal skin from a M. musculus x M. spretus backcross to generate a network view of the gene expression architecture of mouse skin. Here we demonstrate how this approach identifies expression motifs that contribute to tissue organization and biological functions related to inflammation, haematopoiesis, cell cycle control and tumour susceptibility. Motifs associated with inflammation, epidermal barrier function and proliferation are differentially regulated in backcross mice susceptible or resistant to tumour development. The intestinal stem cell marker Lgr5 is identified as a candidate master regulator of the hair follicle, and the vitamin D receptor (Vdr) is linked to coordinated control of epidermal barrier function, inflammation and tumour susceptibility.

}, keywords = {Animals, Cell Cycle, Crosses, Genetic, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Hair Follicle, Hematopoiesis, Inflammation, Male, Mice, Quantitative Trait Loci, Receptors, Calcitriol, Receptors, G-Protein-Coupled, Skin, Skin Neoplasms}, issn = {1476-4687}, doi = {10.1038/nature07683}, author = {Quigley, David A and To, Minh D and Perez-Losada, Jesus and Pelorosso, Facundo G and Jiang-Hua Mao and Nagase, Hiroki and Ginzinger, David G and Balmain, Allan} } @article {166, title = {Identification of hematein as a novel inhibitor of protein kinase CK2 from a natural product library.}, journal = {BMC Cancer}, volume = {9}, year = {2009}, month = {2009}, pages = {135}, abstract = {

BACKGROUND: Casein kinase 2 (CK2) is dysregulated in various human cancers and is a promising target for cancer therapy. To date, there is no small molecular CK2 inhibitor in clinical trial yet. With the aim to identify novel CK2 inhibitors, we screened a natural product library.

METHODS: We adopted cell-based proliferation and CK2 kinase assays to screen CK2 inhibitors from a natural compound library. Dose-dependent response of CK2 inhibitors in vitro was determined by a radioisotope kinase assay. Western blot analysis was used to evaluate down stream Akt phosphorylation and apoptosis. Apoptosis was also evaluated by annexin-V/propidium iodide (PI) labeling method using flow cytometry. Inhibition effects of CK2 inhibitors on the growth of cancer and normal cells were evaluated by cell proliferation and viability assays.

RESULTS: Hematein was identified as a novel CK2 inhibitor that is highly selective among a panel of kinases. It appears to be an ATP non-competitive and partially reversible CK2 inhibitor with an IC50 value of 0.55 muM. In addition, hematein inhibited cancer cell growth partially through down-regulation of Akt phosphorylation and induced apoptosis in these cells. Furthermore, hematein exerted stronger inhibition effects on the growth of cancer cells than in normal cells.

CONCLUSION: In this study, we showed that hematein is a novel selective and cell permeable small molecule CK2 inhibitor. Hematein showed stronger growth inhibition effects to cancer cells when compared to normal cells. This compound may represent a promising class of CK2 inhibitors.

}, keywords = {Adenosine Triphosphate, Apoptosis, Casein Kinase II, Cell Growth Processes, Cell Line, Tumor, Dose-Response Relationship, Drug, HCT116 Cells, HeLa Cells, Hematoxylin, Humans, Lung Neoplasms, Neoplasms, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Substrate Specificity}, issn = {1471-2407}, doi = {10.1186/1471-2407-9-135}, author = {Hung, Ming-Szu and Xu, Zhidong and Lin, Yu-Ching and Jiang-Hua Mao and Yang, Cheng-Ta and Chang, Pey-Jium and Jablons, David M and You, Liang} } @article {163, title = {Atm heterozygosity does not increase tumor susceptibility to ionizing radiation alone or in a p53 heterozygous background.}, journal = {Oncogene}, volume = {27}, year = {2008}, month = {2008 Nov 20}, pages = {6596-600}, abstract = {

Ataxia-Telangiectasia (A-T) is an autosomal recessive human disease characterized by genetic instability, radiosensitivity, immunodeficiency and cancer predisposition, because of mutation in both alleles of the ATM (ataxia-telangiectasia mutated) gene. The role of Atm heterozygosity in cancer susceptibility is controversial, in both human and mouse. Earlier studies identified deletions near the Atm gene on mouse chromosome 9 in radiation-induced lymphomas from p53 heterozygous mice. To determine whether Atm was the target of these deletions, Atm heterozygous as well as Atm/P53 double heterozygous mice were treated with ionizing radiation. There were no significant differences in tumor latency, progression and lifespan after gamma-radiation in Atm heterozygous mice compared with their wild-type control counterparts. Deletions were found on chromosome 9 near the Atm locus in radiation-induced tumors, but in 50\% of the cases the deletion included the knockout allele, and the expression of Atm was maintained in the tumors indicating that loss of heterozygosity on chromosome 9 is not driven by Atm, but by an alternative tumor suppressor gene located near Atm on this chromosome. We conclude that Atm heterozygosity does not confer an increase in tumor susceptibility in this context.

}, keywords = {Animals, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, DNA-Binding Proteins, Genes, p53, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Heterozygote, Loss of Heterozygosity, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasms, Protein-Serine-Threonine Kinases, Radiation Tolerance, Radiation, Ionizing, Tumor Suppressor Proteins}, issn = {1476-5594}, doi = {10.1038/onc.2008.280}, author = {Jiang-Hua Mao and Wu, D and DelRosario, R and Castellanos, A and Balmain, A and Perez-Losada, J} } @article {161, title = {Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer.}, journal = {Am J Pathol}, volume = {172}, year = {2008}, month = {2008 Jan}, pages = {236-46}, abstract = {

The transgenic adenocarcinoma of mouse prostate (TRAMP) model is widely used in prostate cancer research because of rapid tumor onset and progression. The transgenic mouse is on a C57BL/6 (B6) background and expresses SV40 T-antigen under the probasin promoter. The strong genetic component of susceptibility to prostate cancer in humans prompted us to investigate the effect of mouse strain background (FVB and B6) on incidence, progression, and pathology of prostate cancer in this model. Because TRAMP lesions are unique but differ from conventional prostatic intraepithelial neoplasia because the epithelium and stroma are affected diffusely, we designated them as "atypical hyperplasia of Tag." Although the incidence and severity of atypical hyperplasia of Tag is similar, FVB-TRAMP mice live significantly shorter lives than B6-TRAMP mice because of the rapid development and progression of neuroendocrine carcinomas. This is associated with an increased frequency of neuroendocrine precursor lesions in young TRAMP mice, detectable at 4 weeks after birth. These lesions show properties of bipotential stem cells and co-express markers of epithelial (E-cadherin) and neuroendocrine (synaptophysin) lineages, as well as the transcription factors Foxa1 and Foxa2. Transplantation studies using TRAMP prostatic ducts suggested that neuroendocrine carcinomas arise independently from atypical hyperplasias or other epithelial lesions. Adenocarcinomas were not seen in our cohort. Thus, neuroendocrine carcinomas are the principal malignancy in this model and may develop from bipotential progenitor cells at an early stage of prostate tumorigenesis.

}, keywords = {Adenocarcinoma, Animals, Cell Lineage, Disease Models, Animal, Humans, Kidney, Male, Mice, Mice, Nude, Mice, Transgenic, Neoplasm Metastasis, Neoplasms, Glandular and Epithelial, Neuroendocrine Tumors, Prostatic Neoplasms, Transgenes}, issn = {0002-9440}, doi = {10.2353/ajpath.2008.070602}, author = {Chiaverotti, Teresa and Couto, Suzana S and Donjacour, Annemarie and Jiang-Hua Mao and Nagase, Hiroki and Cardiff, Robert D and Cunha, Gerald R and Balmain, Allan} } @article {162, title = {FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression.}, journal = {Science}, volume = {321}, year = {2008}, month = {2008 Sep 12}, pages = {1499-502}, abstract = {

The enzyme mTOR (mammalian target of rapamycin) is a major target for therapeutic intervention to treat many human diseases, including cancer, but very little is known about the processes that control levels of mTOR protein. Here, we show that mTOR is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7. Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN (phosphatase and tensin homolog), which also activates mTOR. Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment, which suggests that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway.

}, keywords = {Animals, Breast Neoplasms, Cell Cycle Proteins, Cell Line, Cell Line, Tumor, F-Box Proteins, Gene Deletion, Gene Dosage, Gene Silencing, Genes, Tumor Suppressor, Humans, Mice, Mice, Nude, Mutation, Neoplasm Transplantation, Phosphorylation, Protein Binding, Protein Kinases, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Transfection, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination}, issn = {1095-9203}, doi = {10.1126/science.1162981}, author = {Jiang-Hua Mao and Kim, Il-Jin and Wu, Di and Climent, Joan and Kang, Hio Chung and DelRosario, Reyno and Balmain, Allan} } @article {164, title = {Sequence divergence of Mus spretus and Mus musculus across a skin cancer susceptibility locus.}, journal = {BMC Genomics}, volume = {9}, year = {2008}, month = {2008}, pages = {626}, abstract = {

BACKGROUND: Mus spretus diverged from Mus musculus over one million years ago. These mice are genetically and phenotypically divergent. Despite the value of utilizing M. musculus and M. spretus for quantitative trait locus (QTL) mapping, relatively little genomic information on M. spretus exists, and most of the available sequence and polymorphic data is for one strain of M. spretus, Spret/Ei. In previous work, we mapped fifteen loci for skin cancer susceptibility using four different M. spretus by M. musculus F1 backcrosses. One locus, skin tumor susceptibility 5 (Skts5) on chromosome 12, shows strong linkage in one cross.

RESULTS: To identify potential candidate genes for Skts5, we sequenced 65 named and unnamed genes and coding elements mapping to the peak linkage area in outbred spretus, Spret/EiJ, FVB/NJ, and NIH/Ola. We identified polymorphisms in 62 of 65 genes including 122 amino acid substitutions. To look for polymorphisms consistent with the linkage data, we sequenced exons with amino acid polymorphisms in two additional M. spretus strains and one additional M. musculus strain generating 40.1 kb of sequence data. Eight candidate variants were identified that fit with the linkage data. To determine the degree of variation across M. spretus, we conducted phylogenetic analyses. The relatedness of the M. spretus strains at this locus is consistent with the proximity of region of ascertainment of the ancestral mice.

CONCLUSION: Our analyses suggest that, if Skts5 on chromosome 12 is representative of other regions in the genome, then published genomic data for Spret/EiJ are likely to be of high utility for genomic studies in other M. spretus strains.

}, keywords = {Amino Acid Substitution, Animals, Chromosome Mapping, Evolution, Molecular, Genetic Linkage, Genetic Predisposition to Disease, Genotype, Mice, Phylogeny, Polymorphism, Genetic, Sequence Alignment, Sequence Analysis, DNA, Skin Neoplasms, Species Specificity}, issn = {1471-2164}, doi = {10.1186/1471-2164-9-626}, author = {Mahler, Kimberly L and Fleming, Jessica L and Dworkin, Amy M and Gladman, Nicholas and Cho, Hee-Yeon and Jiang-Hua Mao and Balmain, Allan and Toland, Amanda Ewart} } @article {160, title = {Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer.}, journal = {Clin Cancer Res}, volume = {13}, year = {2007}, month = {2007 Oct 1}, pages = {5745-55}, abstract = {

PURPOSE: This study was designed to elucidate the role of amplification at 8q24 in the pathophysiology of ovarian and breast cancer because increased copy number at this locus is one of the most frequent genomic abnormalities in these cancers.

EXPERIMENTAL DESIGN: To accomplish this, we assessed the association of amplification at 8q24 with outcome in ovarian cancers using fluorescence in situ hybridization to tissue microarrays and measured responses of ovarian and breast cancer cell lines to specific small interfering RNAs against the oncogene MYC and a putative noncoding RNA, PVT1, both of which map to 8q24.

RESULTS: Amplification of 8q24 was associated with significantly reduced survival duration. In addition, small interfering RNA-mediated reduction in either PVT1 or MYC expression inhibited proliferation in breast and ovarian cancer cell lines in which they were both amplified and overexpressed but not in lines in which they were not amplified/overexpressed. Inhibition of PVT1 expression also induced a strong apoptotic response in cell lines in which it was overexpressed but not in lines in which it was not amplified/overexpressed. Inhibition of MYC, on the other hand, did not induce an apoptotic response in cell lines in which MYC was amplified and overexpressed.

CONCLUSIONS: These results suggest that MYC and PVT1 contribute independently to ovarian and breast pathogenesis when overexpressed because of genomic abnormalities. They also suggest that PVT1-mediated inhibition of apoptosis may explain why amplification of 8q24 is associated with reduced survival duration in patients treated with agents that act through apoptotic mechanisms.

}, keywords = {Apoptosis, Breast Neoplasms, Chromosome Aberrations, Chromosomes, Human, Pair 8, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genome, Humans, In Situ Hybridization, Fluorescence, Ovarian Neoplasms, Proteins, Proto-Oncogene Proteins c-myc, RNA, Long Noncoding, Transcription, Genetic, Treatment Outcome}, issn = {1078-0432}, doi = {10.1158/1078-0432.CCR-06-2882}, author = {Guan, Yinghui and Kuo, Wen-Lin and Stilwell, Jackie L and Takano, Hirokuni and Lapuk, Anna V and Fridlyand, Jane and Jiang-Hua Mao and Yu, Mamie and Miller, Melinda A and Santos, Jennifer L and Kalloger, Steve E and Carlson, Joseph W and Ginzinger, David G and Celniker, Susan E and Mills, Gordon B and Huntsman, David G and Gray, Joe W} } @article {158, title = {Characterization of breast cancer by array comparative genomic hybridization.}, journal = {Biochem Cell Biol}, volume = {85}, year = {2007}, month = {2007 Aug}, pages = {497-508}, abstract = {

Cancer progression is due to the accumulation of recurrent genomic alterations that induce growth advantage and clonal expansion. Most of these genomic changes can be detected using the array comparative genomic hybridization (CGH) technique. The accurate classification of these genomic alterations is expected to have an important impact on translational and basic research. Here we review recent advances in CGH technology used in the characterization of different features of breast cancer. First, we present bioinformatics methods that have been developed for the analysis of CGH arrays; next, we discuss the use of array CGH technology to classify tumor stages and to identify and stratify subgroups of patients with different prognoses and clinical behaviors. We finish our review with a discussion of how CGH arrays are being used to identify oncogenes, tumor suppressor genes, and breast cancer susceptibility genes.

}, keywords = {Breast Neoplasms, Computational Biology, Cytogenetic Analysis, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Humans, Oligonucleotide Array Sequence Analysis, Prognosis}, issn = {0829-8211}, doi = {10.1139/O07-072}, author = {Climent, J and Garcia, J L and Jiang-Hua Mao and Arsuaga, J and Perez-Losada, J} } @article {157, title = {Convergence of congenic mapping and allele-specific alterations in tumors for the resolution of the Skts1 skin tumor susceptibility locus.}, journal = {Oncogene}, volume = {26}, year = {2007}, month = {2007 Jun 14}, pages = {4171-8}, abstract = {

Although several familial cancer genes with high-penetrance mutations have been identified, the major genetic component of susceptibility to sporadic cancers is attributable to low-penetrance alleles. These {\textquoteright}weak{\textquoteright} tumor susceptibility genes do not segregate as single Mendelian traits and are therefore difficult to find in studies of human populations. Previously, we have proposed that a combination of germline mapping and analysis of allele-specific imbalance in tumors may be used to refine the locations of susceptibility genes using mouse models of cancer. Here, we have used linkage analysis and congenic mouse strains to map the major skin tumor susceptibility locus Skts1 within a genetic interval of 0.9 cM on proximal chromosome 7. This interval lies in an apparent recombination cold spot, and corresponds to a physical distance of about 15 Mb. We therefore, used patterns of allele-specific imbalances in tumors from backcross and congenic mice to refine the location of Skts1. We demonstrate that this single tumor modifier locus has a dramatic effect on the allelic preference for imbalance on chromosome 7, with at least 90\% of tumors from the congenics showing preferential gain of markers on the chromosome carrying the susceptibility variant. Importantly, these alterations enabled us to refine the location of Skts1 at higher resolution than that attained using the congenic mice. We conclude that low-penetrance susceptibility genes can have strong effects on patterns of allele-specific somatic genetic changes in tumors, and that analysis of the directionality of these somatic events provides an important and rapid route to identification of germline genetic variants that confer increased cancer risk.

}, keywords = {Alleles, Animals, Cell Line, Genetic Predisposition to Disease, In Situ Hybridization, Fluorescence, Skin Neoplasms}, issn = {0950-9232}, doi = {10.1038/sj.onc.1210206}, author = {de Koning, J P and Wakabayashi, Y and Nagase, H and Jiang-Hua Mao and Balmain, A} } @article {155, title = {Crosstalk between Aurora-A and p53: frequent deletion or downregulation of Aurora-A in tumors from p53 null mice.}, journal = {Cancer Cell}, volume = {11}, year = {2007}, month = {2007 Feb}, pages = {161-73}, abstract = {

The Aurora-A kinase gene is amplified in a subset of human tumors and in radiation-induced lymphomas from p53 heterozygous mice. Normal tissues from p53-/- mice have increased Aurora-A protein levels, but lymphomas from these mice exhibit heterozygous deletions of Aurora-A and/or reduced protein expression. A similar correlation between low p53 levels and Aurora-A gene deletions and expression is found in human breast cancer cell lines. In vitro studies using mouse embryo fibroblasts demonstrate that inhibition of Aurora-A can have either positive or negative effects on cell growth as a function of p53 status. These data have implications for the design of approaches to targeted cancer therapy involving the crosstalk between Aurora-A kinase and p53 pathways.

}, keywords = {Animals, Apoptosis, Aurora Kinase A, Aurora Kinases, Breast Neoplasms, Cells, Cultured, Down-Regulation, Embryo, Mammalian, Female, Fibroblasts, Gene Deletion, Gene Dosage, Gene Expression Profiling, Genomic Instability, Heterozygote, Lymphoma, Male, Mice, Mice, Knockout, Microarray Analysis, Neoplasms, Radiation-Induced, Protein-Serine-Threonine Kinases, Survival Rate, Thymus Neoplasms, Tumor Suppressor Protein p53, Whole-Body Irradiation}, issn = {1535-6108}, doi = {10.1016/j.ccr.2006.11.025}, author = {Jiang-Hua Mao and Wu, Di and Perez-Losada, Jesus and Jiang, Tao and Li, Qian and Neve, Richard M and Gray, Joe W and Cai, Wei-Wen and Balmain, Allan} } @article {159, title = {HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis.}, journal = {Proc Natl Acad Sci U S A}, volume = {104}, year = {2007}, month = {2007 Aug 7}, pages = {13040-5}, abstract = {

Transcriptional control by beta-catenin and lymphoid enhancer-binding factor 1 (LEF1)/T cell factor regulates proliferation in stem cells and tumorigenesis. Here we provide evidence that transcriptional co repressor homeodomain interacting protein kinase 2 (HIPK2) controls the number of stem and progenitor cells in the skin and the susceptibility to develop squamous cell carcinoma. Loss of HIPK2 leads to increased proliferative potential, more rapid G1-S transition in cell cycle, and expansion of the epidermal stem cell compartment. Among the critical regulators of G1-S transition in the cell cycle, only cyclin D1 is selectively up-regulated in cells lacking HIPK2. Conversely, overexpression of HIPK2 suppresses LEF1/beta-catenin-mediated transcriptional activation of cyclin D1 expression. However, deletion of the C-terminal YH domain of HIPK2 completely abolishes its ability to recruit another transcriptional corepressor CtBP and suppress LEF1/beta-catenin-mediated transcription. To determine whether loss of HIPK2 leads to increased susceptibility to tumorigenesis, we treat wild-type, Hipk2+/-, andHipk2-/- mice with the two-stage carcinogenesis protocol. Our results indicate that more skin tumors are induced in Hipk2+/- and Hipk2-/- mutants, with most of the tumors showing shortened incubation time and malignant progression. Together, our results indicate that HIPK2 is a tumor suppressor that controls proliferation by antagonizing LEF1/beta-catenin-mediated transcription. Loss of HIPK2 synergizes with activation of H-ras to induce tumorigenesis.

}, keywords = {Animals, beta Catenin, Carrier Proteins, Cell Proliferation, Cells, Cultured, Cyclin D1, Epidermis, Keratinocytes, Lymphoid Enhancer-Binding Factor 1, Mice, Protein-Serine-Threonine Kinases, Repressor Proteins, Skin Neoplasms, Stem Cells, Transcriptional Activation}, issn = {0027-8424}, doi = {10.1073/pnas.0703213104}, author = {Wei, Guangwei and Ku, Stephen and Ma, Gene K and Saito, Shin{\textquoteright}ichi and Tang, Amy A and Zhang, Jiasheng and Jiang-Hua Mao and Appella, Ettore and Balmain, Allan and Huang, Eric J} } @article {156, title = {Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice.}, journal = {Nature}, volume = {445}, year = {2007}, month = {2007 Feb 15}, pages = {761-5}, abstract = {

Mice of the C57BL/6 strain are resistant to the development of skin squamous carcinomas (SCCs) induced by an activated Ras oncogene, whereas FVB/N mice are highly susceptible. The genetic basis of this difference in phenotype is unknown. Here we show that susceptibility to SCC is under the control of a carboxy-terminal polymorphism in the mouse Ptch gene. F1 hybrids between C57BL/6 and FVB/N strains ((B6FVB)F1) are resistant to Ras-induced SCCs, but resistance can be overcome either by elimination of the C57BL/6 Ptch allele (Ptch(B6)) or by overexpression of the FVB/N Ptch allele (Ptch(FVB)) in the epidermis of K5Hras-transgenic (B6FVB)F1 hybrid mice. The human Patched (PTCH) gene is a classical tumour suppressor gene for basal cell carcinomas and medulloblastomas, the loss of which causes increased signalling through the Sonic Hedgehog (SHH) pathway. SCCs that develop in PtchB6+/- mice do not lose the wild-type Ptch gene or show evidence of increased SHH signalling. Although Ptch(FVB) overexpression can promote SCC formation, continued expression is not required for tumour maintenance, suggesting a role at an early stage of tumour cell lineage commitment. The Ptch polymorphism affects Hras-induced apoptosis, and binding to Tid1, the mouse homologue of the Drosophila l(2)tid tumour suppressor gene. We propose that Ptch occupies a critical niche in determining basal or squamous cell lineage, and that both tumour types can arise from the same target cell depending on carcinogen exposure and host genetic background.

}, keywords = {Amino Acid Sequence, Animals, Apoptosis, Carcinoma, Squamous Cell, Cell Line, Cell Transformation, Neoplastic, Crosses, Genetic, Female, Gene Expression Regulation, Neoplastic, Genes, ras, HSP40 Heat-Shock Proteins, Humans, Kruppel-Like Transcription Factors, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Polymorphism, Genetic, ras Proteins, Receptors, Cell Surface}, issn = {1476-4687}, doi = {10.1038/nature05489}, author = {Wakabayashi, Yuichi and Jiang-Hua Mao and Brown, Ken and Girardi, Michael and Balmain, Allan} } @article {154, title = {A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice.}, journal = {Nat Genet}, volume = {38}, year = {2006}, month = {2006 Aug}, pages = {926-30}, abstract = {

Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1). Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors and is a candidate Pas1 gene. M. spretus mice (SPRET/Ei) carry a Pas1 resistance haplotype for chemically induced lung tumors. We demonstrate that the SPRET/Ei Pas1 allele is switched from resistance to susceptibility by fixation of the parental origin of the mutant Kras2 allele. This switch correlates with low expression of endogenous Kras2 in SPRET/Ei. We propose that the Pas1 modifier effect is due to Kras2, and that a sensitive balance between the expression levels of wild-type and mutant alleles determines lung tumor susceptibility. These data demonstrate that cancer predisposition should also be considered in the context of somatic events and could have major implications for the design of human association studies to identify cancer susceptibility genes.

}, keywords = {Adenoma, Alleles, Animals, Carcinogens, Female, Genetic Predisposition to Disease, Lung Neoplasms, Male, Mice, Models, Genetic, Mutation, Oncogenes, Proto-Oncogene Proteins p21(ras), Risk Factors, Urethane}, issn = {1061-4036}, doi = {10.1038/ng1836}, author = {To, Minh D and Perez-Losada, Jesus and Jiang-Hua Mao and Hsu, Jeff and Jacks, Tyler and Balmain, Allan} } @article {153, title = {Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility.}, journal = {Proc Natl Acad Sci U S A}, volume = {103}, year = {2006}, month = {2006 May 23}, pages = {8125-30}, abstract = {

The human TGFB1 gene is polymorphic, and genetic variants are associated with altered cancer risk. However, human genetic association studies have had variable outcomes because TGFbeta1 action is context-dependent. We used the murine skin model of chemical carcinogenesis in genetic linkage analysis of three independent Mus musculus NIH/Ola x (Mus spretus x M. musculus NIH/Ola)F1 backcrosses, to identify a skin tumor susceptibility locus, Skts14, on proximal chromosome 7. Tgfb1 maps at the peak of linkage. The mouse Tgfb1 gene is polymorphic, resulting in cis-regulated differential allelic mRNA expression between M. spretus and M. musculus in F1 mouse skin. This phenomenon is reflected in differential phospho-SMAD2 levels, downstream of TGFbeta signaling, between these two mouse species. In normal F1 mouse skin, the Tgfb1SPR allele is expressed at higher levels than the Tgfb1NIH allele, and this differential is accentuated by phorbol 12-myristate 13-acetate treatment. In benign F1 papillomas, this imbalance is reversed, possibly by selection against expression of a hyperactive Tgfb1SPR allele in TGFbeta growth-responsive tumors. We demonstrate that skin tumor susceptibility is altered by Tgfb1 gene dosage, but that manifestation of Tgfb1-linked skin tumor susceptibility in M. musculus NIH/Ola x (M. spretus x M. musculus NIH/Ola)F1 backcross mice depends on interactions with another unlinked tumor modifying locus, Skts15, that overlaps Tgfbm3 on chromosome 12. These findings illustrate the power of complex genetic interactions in determining disease outcome and have major implications to the assessment of disease risk in individuals harboring variant TGFB1 alleles.

}, keywords = {Alleles, Animals, Chromosome Mapping, Crosses, Genetic, Genetic Linkage, Genetic Predisposition to Disease, Genetic Variation, Homozygote, Mice, Polymorphism, Genetic, Skin, Skin Neoplasms, Transforming Growth Factor beta}, issn = {0027-8424}, doi = {10.1073/pnas.0602581103}, author = {Jiang-Hua Mao and Saunier, Elise F and de Koning, John P and McKinnon, Margaret M and Higgins, Mamie Nakijama and Nicklas, Kathy and Yang, Hai-Tao and Balmain, Allan and Akhurst, Rosemary J} } @article {149, title = {Control of genomic instability and epithelial tumor development by the p53-Fbxw7/Cdc4 pathway.}, journal = {Cancer Res}, volume = {65}, year = {2005}, month = {2005 Aug 1}, pages = {6488-92}, abstract = {

Mouse models of cancer have provided novel insights into the timing of p53 loss during tumorigenesis. We have recently identified Fbxw7/Cdc4 as a downstream target of p53 loss that controls genomic instability and tumor development in epithelial tumors. Although p53-deficient mice primarily develop lymphomas and sarcomas, the additional loss of one copy of the Fbxw7 gene drives tumor development in a range of epithelial tissues. These data highlight the importance of genetic instability at the chromosome level in the development of common cancer types, and further illustrate the value of mouse models in identifying causal genetic events in epithelial tumor formation.

}, keywords = {Animals, Cell Cycle Proteins, Disease Models, Animal, DNA Damage, F-Box Proteins, Fibrosarcoma, Genes, p53, Genomic Instability, Humans, Loss of Heterozygosity, Lymphoma, Mice, Ubiquitin-Protein Ligases}, issn = {0008-5472}, doi = {10.1158/0008-5472.CAN-05-1294}, author = {Perez-Losada, Jesus and Jiang-Hua Mao and Balmain, Allan} } @article {151, title = {Crosstalk between Pten and Ras signaling pathways in tumor development.}, journal = {Cell Cycle}, volume = {4}, year = {2005}, month = {2005 Sep}, pages = {1185-8}, abstract = {

The Pten and Ras pathways are disrupted or activated, respectively, in a substantial proportion of cancers. Skin tumors induced by the classical two stage carcinogenesis protocols show consistent activating mutations of the H-ras gene, but in tumors from Pten heterozygous mice, the frequency of these mutations is markedly decreased, suggesting some redundancy between these pathways. Pten heterozygous mice develop more papillomas and have earlier onset of carcinomas than their control counterparts, but molecular analysis of these tumors indicated that complete loss of Pten and activation of H-ras are mutually exclusive. Pten loss is however not functionally equivalent to H-ras activation, as Pten-/- tumors occur earlier and are generally more aggressive. Tumors with Pten loss or H-ras activation have different biochemical properties, suggestive of alternative routes to malignancy. These findings in this mouse model have important implications for the rational design of new targeted therapies for human tumors.

}, keywords = {Animals, Carcinoma, Gene Expression Regulation, Neoplastic, Heterozygote, Humans, Mice, Models, Biological, Mutation, Neoplasms, Proto-Oncogene Proteins p21(ras), PTEN Phosphohydrolase, ras Proteins, Signal Transduction, Skin Neoplasms, Stem Cells, Transgenes}, issn = {1551-4005}, doi = {10.4161/cc.4.9.2039}, author = {To, Minh D and Perez-Losada, Jesus and Jiang-Hua Mao and Balmain, Allan} } @article {148, title = {Epigenome analyses using BAC microarrays identify evolutionary conservation of tissue-specific methylation of SHANK3.}, journal = {Nat Genet}, volume = {37}, year = {2005}, month = {2005 Jun}, pages = {645-51}, abstract = {

CpG islands are present in one-half of all human and mouse genes and typically overlap with promoters or exons. We developed a method for high-resolution analysis of the methylation status of CpG islands genome-wide, using arrays of BAC clones and the methylation-sensitive restriction enzyme NotI. Here we demonstrate the accuracy and specificity of the method. By computationally mapping all NotI sites, methylation events can be defined with single-nucleotide precision throughout the genome. We also demonstrate the unique expandability of the array method using a different methylation-sensitive restriction enzyme, BssHII. We identified and validated new CpG island loci that are methylated in a tissue-specific manner in normal human tissues. The methylation status of the CpG islands is associated with gene expression for several genes, including SHANK3, which encodes a structural protein in neuronal postsynaptic densities. Defects in SHANK3 seem to underlie human 22q13 deletion syndrome. Furthermore, these patterns for SHANK3 are conserved in mice and rats.

}, keywords = {Animals, Carrier Proteins, Chromosomes, Artificial, Bacterial, Conserved Sequence, CpG Islands, Deoxyribonucleases, Type II Site-Specific, DNA Methylation, Humans, Mice, Nerve Tissue Proteins, Oligonucleotide Array Sequence Analysis, Organ Specificity, Regulatory Sequences, Nucleic Acid, Reverse Transcriptase Polymerase Chain Reaction}, issn = {1061-4036}, doi = {10.1038/ng1563}, author = {Ching, Tsui-Ting and Maunakea, Alika K and Jun, Peter and Hong, Chibo and Zardo, Giuseppe and Pinkel, Daniel and Albertson, Donna G and Fridlyand, Jane and Jiang-Hua Mao and Shchors, Ksenya and Weiss, William A and Costello, Joseph F} } @article {152, title = {Genomic instability in radiation-induced mouse lymphoma from p53 heterozygous mice.}, journal = {Oncogene}, volume = {24}, year = {2005}, month = {2005 Nov 24}, pages = {7924-34}, abstract = {

Although radiation can directly induce DNA damage and is a known human and animal carcinogen, the number of genetic changes in radiation-induced tumors, and the pathways responsible for generating them, are unknown. We have used high-density BAC arrays covering >95\% of the mouse genome for analysis of genomic patterns of aberrations in spontaneous and radiation-induced mouse lymphomas. The majority of radiation-induced tumors exhibit one of three {\textquoteright}signatures{\textquoteright} based on gene copy number changes. Some exhibit extensive scrambling of the genome, with very high numbers of recurrent gains and losses. Two other signatures are characterized by excess gains but relatively few losses, or vice versa. Changes in spontaneous tumors often involve whole chromosomes, whereas radiation-induced tumors exhibit a high frequency of localized deletion/amplification events. The number of copy number abnormalities does not correlate with the latency or pathology of the tumors. We propose that specific early events following radiation exposure induce changes in {\textquoteright}caretaker{\textquoteright} genes that control specific downstream pathways involved in DNA damage repair. The nature of these early events may determine the overall genomic signature observed in the resulting tumor.

}, keywords = {Animals, DNA Damage, DNA Repair, Female, Gene Amplification, Gene Deletion, Gene Expression Profiling, Genes, p53, Genomic Instability, Lymphoma, Male, Mice, Mice, Inbred C57BL, Neoplasms, Radiation-Induced, Thymus Neoplasms}, issn = {0950-9232}, doi = {10.1038/sj.onc.1208926}, author = {Jiang-Hua Mao and Li, Jiangzhen and Jiang, Tao and Li, Qian and Wu, Di and Perez-Losada, Jesus and DelRosario, Reyno and Peterson, Leif and Balmain, Allan and Cai, Wei-Wen} } @article {147, title = {Mapping segmental and sequence variations among laboratory mice using BAC array CGH.}, journal = {Genome Res}, volume = {15}, year = {2005}, month = {2005 Feb}, pages = {302-11}, abstract = {

We used arrays of 2069 BACs (1303 nonredundant autosomal clones) to map sequence variation among Mus spretus (SPRET/Ei and SPRET/Glasgow) and Mus musculus (C3H/HeJ, BALB/cJ, 129/J, DBA/2J, NIH, FVB/N, and C57BL/6) strains. We identified 80 clones representing 74 autosomal loci of copy number variation (|log(2)ratio| >/= 0.4). These variant loci distinguish laboratory strains. By FISH mapping, we determined that 63 BACs mapped to a single site on C57BL/6J chromosomes, while 17 clones mapped to multiple chromosomes (n = 16) or multiple sites on one chromosome (n = 1). We also show that small ratio changes (Delta log(2)ratio approximately 0.1) distinguish homozygous and heterozygous regions of the genome in interspecific backcross mice, providing an efficient method for genotyping progeny of backcrosses.

}, keywords = {Animals, Chromosome Mapping, Chromosomes, Artificial, Bacterial, Crosses, Genetic, Gene Dosage, Genetic Markers, Genetic Variation, Genome, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Inbred Strains, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Species Specificity}, issn = {1088-9051}, doi = {10.1101/gr.2902505}, author = {A Snijders and Nowak, Norma J and Huey, Bing and Fridlyand, Jane and Law, Sindy and Conroy, Jeffrey and Tokuyasu, Taku and Demir, Kubilay and Chiu, Readman and Jiang-Hua Mao and Jain, Ajay N and Jones, Steven J M and Balmain, Allan and Pinkel, Daniel and Albertson, Donna G} } @article {150, title = {p63 and p73 do not contribute to p53-mediated lymphoma suppressor activity in vivo.}, journal = {Oncogene}, volume = {24}, year = {2005}, month = {2005 Aug 18}, pages = {5521-4}, abstract = {

p53 is one of the most important tumor suppressor genes in human cancer, but the roles of its homologues p63 and p73 in tumor suppression, alone or in collaboration with p53, remains controversial. Both p63 and p73 can be deregulated after DNA damage, and induce cell cycle arrest and apoptosis, but mice carrying inactive alleles of these genes do not develop spontaneous tumors. Since heterozygous loss of p53 confers strong sensitization to radiation-induced lymphoma development, we investigated the possibility that radiation exposure may reveal previously undetected tumor suppressor properties in p63 or p73, alone or in combination with p53. Animals heterozygous for p63 or p73, as well as both double heterozygous p53/p63 or p53/p73 mice, showed no significant differences in tumor latency, spectrum or frequency after gamma-radiation, compared to their control counterparts. Deletions were found near the p63 locus on chromosome 16 in radiation-induced tumors, but these frequently included the knockout allele. No deletions or LOH involving the p73 gene were detected, and expression of both genes was maintained in the tumors. We conclude that p53 homologues do not contribute to p53 tumor suppressor activity in lymphoma development.

}, keywords = {Animals, Base Sequence, DNA-Binding Proteins, Genes, Tumor Suppressor, Loss of Heterozygosity, Lymphoma, Mice, Mice, Knockout, Molecular Sequence Data, Neoplasms, Radiation-Induced, Nuclear Proteins, Phosphoproteins, Reverse Transcriptase Polymerase Chain Reaction, Trans-Activators, Tumor Suppressor Protein p53, Tumor Suppressor Proteins}, issn = {0950-9232}, doi = {10.1038/sj.onc.1208799}, author = {Perez-Losada, Jesus and Wu, Di and DelRosario, Reyno and Balmain, Allan and Jiang-Hua Mao} } @article {146, title = {Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene.}, journal = {Nature}, volume = {432}, year = {2004}, month = {2004 Dec 9}, pages = {775-9}, abstract = {

The FBXW7/hCDC4 gene encodes a ubiquitin ligase implicated in the control of chromosome stability. Here we identify the mouse Fbxw7 gene as a p53-dependent tumour suppressor gene by using a mammalian genetic screen for p53-dependent genes involved in tumorigenesis. Radiation-induced lymphomas from p53+/- mice, but not those from p53-/- mice, show frequent loss of heterozygosity and a 10\% mutation rate of the Fbxw7 gene. Fbxw7+/- mice have greater susceptibility to radiation-induced tumorigenesis, but most tumours retain and express the wild-type allele, indicating that Fbxw7 is a haploinsufficient tumour suppressor gene. Loss of Fbxw7 alters the spectrum of tumours that develop in p53 deficient mice to include a range of tumours in epithelial tissues such as the lung, liver and ovary. Mouse embryo fibroblasts from Fbxw7-deficient mice, or wild-type mouse cells expressing Fbxw7 small interfering RNA, have higher levels of Aurora-A kinase, c-Jun and Notch4, but not of cyclin E. We propose that p53-dependent loss of Fbxw7 leads to genetic instability by mechanisms that might involve the activation of Aurora-A, providing a rationale for the early occurrence of these mutations in human cancers.

}, keywords = {Animals, Base Sequence, Cell Cycle Proteins, Cell Transformation, Neoplastic, F-Box Proteins, Female, Fibroblasts, Gene Deletion, Genes, Tumor Suppressor, Loss of Heterozygosity, Male, Mice, Mice, Knockout, Mutation, Neoplasms, RNA, Messenger, RNA, Small Interfering, Survival Rate, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases}, issn = {1476-4687}, doi = {10.1038/nature03155}, author = {Jiang-Hua Mao and Perez-Losada, Jesus and Wu, Di and DelRosario, Reyno and Tsunematsu, Ryosuke and Nakayama, Keiichi I and Brown, Ken and Bryson, Sheila and Balmain, Allan} } @article {145, title = {Genomic segmental polymorphisms in inbred mouse strains.}, journal = {Nat Genet}, volume = {36}, year = {2004}, month = {2004 Sep}, pages = {952-4}, abstract = {

By analyzing genomic copy-number differences using high-resolution mouse whole-genome BAC arrays, we uncover substantial differences in regional DNA content between inbred strains of mice. The identification of these apparently common segmental polymorphisms suggests that these differences can contribute to genetic variability and pathologic susceptibility.

}, keywords = {Animals, Base Sequence, Chromosomes, Artificial, Bacterial, Gene Dosage, In Situ Hybridization, Fluorescence, Mice, Mice, Inbred Strains, Polymorphism, Genetic}, issn = {1061-4036}, doi = {10.1038/ng1417}, author = {Li, Jiangzhen and Jiang, Tao and Jiang-Hua Mao and Balmain, Allan and Peterson, Leif and Harris, Charles and Rao, Pulivarthi H and Havlak, Paul and Gibbs, Richard and Cai, Wei-Wen} } @article {144, title = {A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors.}, journal = {Cancer Res}, volume = {64}, year = {2004}, month = {2004 Aug 15}, pages = {5527-34}, abstract = {

Whereas accepted models of tumorigenesis exist for genetic lesions, the timing of epigenetic alterations in cancer is not clearly understood. We have analyzed the profile of aberrations in DNA methylation occurring in cells lines and primary tumors of one of the best-characterized mouse carcinogenesis systems, the multistage skin cancer progression model. Initial analysis using high-performance capillary electrophoresis and immunolocalization revealed a loss of genomic 5-methylcytosine associated with the degree of tumor aggressiveness. Paradoxically, this occurs in the context of a growing number of hypermethylated CpG islands of tumor suppressor genes at the most malignant stages of carcinogenesis. We have observed this last phenomenon using two approaches, a candidate gene approach, studying genes with well-known methylation-associated silencing in human tumors, and a mouse cDNA microarray expression analysis after treatment with DNA demethylating drugs. The transition from epithelial to spindle cell morphology is particularly associated with major epigenetic alterations, such as E-cadherin methylation, demethylation of the Snail promoter, and a decrease of the global DNA methylation. Analysis of data obtained from the cDNA microarray strategy led to the identification of new genes that undergo methylation-associated silencing and have growth-inhibitory effects, such as the insulin-like growth factor binding protein-3. Most importantly, all of the above genes were also hypermethylated in human cancer cell lines and primary tumors, underlining the value of the mouse skin carcinogenesis model for the study of aberrant DNA methylation events in cancer cells.

}, keywords = {5-Methylcytosine, Animals, Cell Line, Tumor, DNA Methylation, DNA Modification Methylases, DNA, Neoplasm, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, Tumor Suppressor, Histones, Humans, Insulin-Like Growth Factor Binding Protein 3, LIM Domain Proteins, Mice, Muscle Proteins, Nuclear Proteins, Oligonucleotide Array Sequence Analysis, Skin Neoplasms}, issn = {0008-5472}, doi = {10.1158/0008-5472.CAN-03-4061}, author = {Fraga, Mario F and Herranz, Michel and Espada, Jes{\'u}s and Ballestar, Esteban and Paz, Maria F and Ropero, Santiago and Erkek, Emel and Bozdogan, Onder and Peinado, H{\'e}ctor and Niveleau, Alain and Jiang-Hua Mao and Balmain, Alan and Cano, Amparo and Esteller, Manel} } @article {143, title = {Mutually exclusive mutations of the Pten and ras pathways in skin tumor progression.}, journal = {Genes Dev}, volume = {18}, year = {2004}, month = {2004 Aug 1}, pages = {1800-5}, abstract = {

Pten heterozygous (Pten+/-) mice develop increased papilloma numbers and show decreased carcinoma latency time in comparison with controls after skin treatment with dimethyl benzanthracene (DMBA) and tetradecanoyl-phorbol acetate (TPA). H-ras mutation is normally a hallmark of DMBA-TPA-induced skin tumors, but 70\% of carcinomas from Pten+/- mice do not exhibit this mutation, and in all cases have lost the wild-type Pten allele. Tumors that retain the Pten wild-type allele also have H-ras mutations, indicating that activation of H-ras and complete loss of Pten are mutually exclusive events in skin carcinomas. Mitogen-activated protein kinase (MAPK) is consistently activated in the tumors with H-ras mutations, but is strongly down-regulated in Pten-/- tumors, suggesting that this pathway is dispensable for skin carcinoma formation. These data have important implications in designing individual therapeutic strategies for the treatment of cancer.

}, keywords = {9,10-Dimethyl-1,2-benzanthracene, Animals, Disease Progression, Genes, ras, Heterozygote, Homozygote, Loss of Heterozygosity, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinases, Mutation, Papilloma, Protein Tyrosine Phosphatases, PTEN Phosphohydrolase, Signal Transduction, Skin Neoplasms, Tetradecanoylphorbol Acetate, Tumor Suppressor Proteins}, issn = {0890-9369}, doi = {10.1101/gad.1213804}, author = {Jiang-Hua Mao and To, Minh D and Perez-Losada, Jesus and Wu, Di and Del Rosario, Reyno and Balmain, Allan} } @article {141, title = {Allele-specific Hras mutations and genetic alterations at tumor susceptibility loci in skin carcinomas from interspecific hybrid mice.}, journal = {Cancer Res}, volume = {63}, year = {2003}, month = {2003 Aug 15}, pages = {4849-53}, abstract = {

We have investigated the effects of germ-line variants that influence skin tumor susceptibility loci on the patterns of somatic genetic alterations in mouse skin cancers. Using a two-stage skin carcinogenesis model, we previously identified at least 13 skin tumor susceptibility (Skts) loci in a large interspecific F1 backcross [(NIH/Ola x M. spretus) x NIH/Ola] study. In this report, we describe the analysis of allele-specific alterations at these loci in skin tumors from the same backcross animals. The mouse Hras gene, located close to Skts2 on chromosome 7, had specific activating mutations in the Mus musculus allele in 23 of 26 carcinomas. In all cases, tumors with Hras mutations also showed specific imbalance of chromosome 7 markers that favored the chromosome carrying the mutant allele. Allele-specific quantitative microsatellite analysis was also carried out, using DNA from 62 carcinomas from (NIH/Ola x M. spretus) x NIH/Ola mice. Frequent allelic imbalance was detected at five additional tumor-susceptibility loci on chromosomes 4, 6, 7, 9, and 16 (Skts7, Skts12, Skts1, Skts6, and Skts9, respectively). At all except Skts7, we found loss of the allele inherited from the resistant strain or amplification of the allele from the susceptible strain. We conclude that polymorphisms in some low-penetrance tumor modifier genes are reflected in the pattern of somatic alterations in tumors. Analysis of such allele-specific changes in tumors may facilitate the identification of functional germ-line variants that control tumor susceptibility.

}, keywords = {Alleles, Animals, Chromosome Mapping, Crosses, Genetic, Female, Genes, ras, Genetic Predisposition to Disease, Mice, Mutation, Skin Neoplasms}, issn = {0008-5472}, author = {Nagase, Hiroki and Jiang-Hua Mao and Balmain, Allan} } @article {142, title = {Genetic interactions between Pten and p53 in radiation-induced lymphoma development.}, journal = {Oncogene}, volume = {22}, year = {2003}, month = {2003 Nov 20}, pages = {8379-85}, abstract = {

Genetic analysis of radiation-induced lymphomas from p53 heterozygous or null mice has revealed a high frequency of genetic alterations on mouse chromosome 19. Detailed microsatellite analysis of chromosome 19 deletions identified three independent regions of loss of heterozygosity, one of which was refined to a 0.3 Mb interval that contained the Pten tumor suppressor gene. More than 50\% of radiation-induced tumors from p53+/- and p53-/- mice showed heterozygous loss of one Pten allele. In most cases, the remaining allele was wild type and expressed, suggesting that Pten is a haploinsufficient tumor suppressor gene for mouse lymphoma development. This conclusion was supported by the detection of specific intragenic deletions in Pten in tumors that retained one wild-type allele. Pten heterozygous mice were just as sensitive as p53+/- mice to induction of tumors by radiation, and surprisingly, the double p53+/-Pten+/-mice were equivalent to p53 null mice in radiation sensitivity. Despite the fact that Pten appears to be a haploinsufficient tumor suppressor gene, most tumors from both the single and double heterozygous mice had lost the remaining wild-type allele. The mechanism of loss in all cases involved the complete chromosome, suggesting that it is driven by other tumor suppressor genes on this chromosome. This sensitized screen therefore identified complementary roles for Pten and p53 pathways in suppression of tumor development induced by radiation exposure.

}, keywords = {Animals, Blotting, Western, Loss of Heterozygosity, Lymphoma, Mice, Neoplasms, Radiation-Induced, Phosphoric Monoester Hydrolases, PTEN Phosphohydrolase, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins}, issn = {0950-9232}, doi = {10.1038/sj.onc.1207083}, author = {Jiang-Hua Mao and Wu, Di and Perez-Losada, Jesus and Nagase, Hiroki and DelRosario, Reyno and Balmain, Allan} } @article {139, title = {Genomic approaches to identification of tumour-susceptibility genes using mouse models.}, journal = {Curr Opin Genet Dev}, volume = {13}, year = {2003}, month = {2003 Feb}, pages = {14-9}, abstract = {

Individual susceptibility to cancer in humans is determined by complex interactions between germline genetic variation and levels of exposure to environmental carcinogens or tumour promoters. Only a small fraction of cancer susceptibility is inherited in a Mendelian manner (high-penetrance familial cancer), and most tumours result from the combined effects of many gene-gene and gene-environment interactions. The sequencing of the mouse genome provides new approaches to one of the most challenging tasks of cancer genetics today.

}, keywords = {Animals, Chromosome Mapping, Disease Models, Animal, Genetic Predisposition to Disease, Genomics, Humans, Mice, Neoplasms, Oligonucleotide Array Sequence Analysis, Quantitative Trait Loci}, issn = {0959-437X}, author = {Jiang-Hua Mao and Balmain, Allan} } @article {140, title = {Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human.}, journal = {Nat Genet}, volume = {34}, year = {2003}, month = {2003 Aug}, pages = {403-12}, abstract = {

Linkage analysis and haplotype mapping in interspecific mouse crosses (Mus musculus x Mus spretus) identified the gene encoding Aurora2 (Stk6 in mouse and STK15 in human) as a candidate skin tumor susceptibility gene. The Stk6 allele inherited from the susceptible M. musculus parent was overexpressed in normal cells and preferentially amplified in tumor cells from F(1) hybrid mice. We identified a common genetic variant in STK15 (resulting in the amino acid substitution F31I) that is preferentially amplified and associated with the degree of aneuploidy in human colon tumors. The Ile31 variant transforms rat1 cells more potently than the more common Phe31 variant. The E2 ubiquitin-conjugating enzyme UBE2N was a preferential binding partner of the {\textquoteright}weak{\textquoteright} STK15 Phe31 variant form in yeast two-hybrid screens and in human cells. This interaction results in colocalization of UBE2N with STK15 at the centrosomes during mitosis. These results are consistent with an important role for the Ile31 variant of STK15 in human cancer susceptibility.

}, keywords = {Aneuploidy, Animals, Aurora Kinase A, Aurora Kinases, Cell Division, Chromosome Mapping, Chromosomes, Human, Pair 20, Crosses, Genetic, Gene Amplification, Genetic Variation, Haplotypes, Humans, In Vitro Techniques, Ligases, Mice, Mice, Inbred Strains, Muridae, Oncogenes, Physical Chromosome Mapping, Protein-Serine-Threonine Kinases, Recombinant Proteins, Skin Neoplasms, Two-Hybrid System Techniques, Ubiquitin-Conjugating Enzymes}, issn = {1061-4036}, doi = {10.1038/ng1220}, author = {Ewart-Toland, Amanda and Briassouli, Paraskevi and de Koning, John P and Jiang-Hua Mao and Yuan, Jinwei and Chan, Florence and MacCarthy-Morrogh, Lucy and Ponder, Bruce A J and Nagase, Hiroki and Burn, John and Ball, Sarah and Almeida, Maria and Linardopoulos, Spiros and Balmain, Allan} } @article {138, title = {Novel approaches to identify low-penetrance cancer susceptibility genes using mouse models.}, journal = {Recent Results Cancer Res}, volume = {163}, year = {2003}, month = {2003}, pages = {19-27; discussion 264-6}, abstract = {

Studies of cancer predisposition have largely concentrated on the role of high-penetrance susceptibility genes. Less than 10\% of the total human tumor burden, however, is accounted for by mutations in these genes. More genetic variation in cancer risk is likely to be due to commoner but lower penetrance alleles. In man, such modifier genes will be difficult to find since they do not segregate as single Mendelian traits. The mouse offers a powerful system for studying polygenic traits such as cancer and has been widely used for this purpose. Novel approaches that might accelerate the identification of these low-penetrance cancer susceptibility genes by using mouse models will be discussed.

}, keywords = {Alleles, Animals, Disease Models, Animal, Genes, Tumor Suppressor, Genetic Linkage, Genetic Predisposition to Disease, Humans, Multifactorial Inheritance, Mutation, Neoplasms, Penetrance, Phenotype, Quantitative Trait Loci}, issn = {0080-0015}, author = {de Koning, John P and Jiang-Hua Mao and Balmain, Allan} } @article {137, title = {Genome-wide detection of chromosomal imbalances in tumors using BAC microarrays.}, journal = {Nat Biotechnol}, volume = {20}, year = {2002}, month = {2002 Apr}, pages = {393-6}, abstract = {

Chromosomal imbalances such as deletions and amplifications are common rearrangements in most tumors. Specific rearrangements are consistently associated with specific tumor types or stages, implicating the role of the genes in a region of chromosomal imbalance in tumor initiation and progression. The development of comparative genomic hybridization (CGH) has obviated the need to obtain metaphase spreads from tumors, so that the chromosomal imbalances in many solid tumors may be revealed using an extracted genomic DNA sample. However, the resolution of the cytogenetic method remains and the extreme technical difficulty of CGH has restricted its use. Conceptually, DNA microarray-based CGH is an obvious solution to all of the limitations of conventional CGH. Although arrays have been used for CGH studies, their success has been limited by poor specific signal-to-noise ratios. Here we demonstrate a microarray-based CGH method that allows reliable detection of chromosomal deletions and amplifications with high resolution. Our microarray system is fundamentally different from most current microarray technologies in that activated DNA is printed on natural glass surfaces while other systems almost exclusively focus on activating the surfaces, a strategy that invariably introduces hybridization backgrounds. The concept of using pre-modification may be generally applied for making arrays of other biological materials, as modifying the substrates will be more controllable in solution than on surfaces.

}, keywords = {Animals, Chromosome Aberrations, Chromosomes, Artificial, Bacterial, Female, Fluorescent Antibody Technique, Genome, Genomics, Genotype, Loss of Heterozygosity, Lymphoma, Male, Mice, Microsatellite Repeats, Oligonucleotide Array Sequence Analysis}, issn = {1087-0156}, doi = {10.1038/nbt0402-393}, author = {Cai, Wei-Wen and Jiang-Hua Mao and Chow, Chi-Wen and Damani, Shamsha and Balmain, Allan and Bradley, Allan} } @article {136, title = {The effect of tissue-specific growth patterns of target stem cells on the spectrum of tumours resulting from multistage tumorigenesis.}, journal = {J Theor Biol}, volume = {210}, year = {2001}, month = {2001 May 7}, pages = {93-100}, abstract = {

A multistage mathematical model of tumorigenesis has been developed to explore the effects of target cell growth pattern on the proportions of tumours deriving from different tissues (the tumour spectrum). Analytical modelling techniques have shown that the effect of the target cell growth pattern on the tumour spectrum also depends on the number of stages (gene mutations) necessary for malignant change in cells of each tissue type. This suggests the existence of temporal "windows of opportunity" for tumours of different types in relation to stage number and growth kinetics. Models of this kind are applicable to cancer-prone transgenic (e.g. p53 deficient) mice, where homozygotes and heterozygotes differ in one carcinogenic stage, and differ also in the spectrum of tumours observed. Generally, tumours deriving from target stem cells which are developmentally short-lived will arise more frequently in homozygotes than heterozygotes. Such models may also be applicable to human syndromes (e.g. Li-Fraumeni) in which susceptibility to cancer is inherited.

}, keywords = {Animals, Cell Division, Genes, p53, Genetic Predisposition to Disease, Humans, Mice, Mice, Transgenic, Models, Animal, Models, Genetic, Mutagenesis, Neoplasms, Neoplastic Stem Cells}, issn = {0022-5193}, doi = {10.1006/jtbi.2001.2300}, author = {Jiang-Hua Mao and Lindsay, K A and Mairs, R J and Wheldon, T E} } @article {135, title = {Epistatic interactions between skin tumor modifier loci in interspecific (spretus/musculus) backcross mice.}, journal = {Cancer Res}, volume = {61}, year = {2001}, month = {2001 Feb 15}, pages = {1305-8}, abstract = {

The development of cancer is influenced both by exposure to environmental carcinogens and by the host genetic background. Epistatic interactions between genes are important in determining phenotype in plant and animal systems and are likely to be major contributors to cancer susceptibility in humans. Several tumor modifier loci have been identified from studies of mouse models of human cancer, and genetic interactions between modifier loci have been detected by genome scanning using recombinant congenic strains of mice (R. Fijneman et al., Nat. Genet., 14: 465-467, 1996; T. van Wezel et al., Nat. Genet., 14: 468-470, 1996; W. N. Frankel et al., Nat. Genet., 14, 371-373, 1996). We demonstrate here that strong genetic interactions between skin tumor modifier loci can be detected by hierarchical whole genome scanning of a complete interspecific backcross [outbred Mus spretus X Mus musculus (NIH/Ola)]. A locus on chromosome 7 (Skts1) showed a highly significant interaction with Skts5 on chromosome 12 (P < 10(-16)), whereas additional significant interactions were detected between loci on chromosomes 4 and 5, and 16 and 15. Some of these quantitative trait loci and their interactions, in particular the Skts1-Skts5 interaction, were confirmed in two completely independent backcrosses using inbred spretus strains (SEG/Pas and SPRET/Ei) and NIH/Ola. These results, therefore, illustrate the general use of interspecific crosses between Mus musculus and Mus spretus for the detection of strong genetic interactions between tumor modifier genes.

}, keywords = {Animals, Epistasis, Genetic, Female, Genetic Linkage, Genetic Predisposition to Disease, Inbreeding, Male, Mice, Papilloma, Skin Neoplasms}, issn = {0008-5472}, author = {Nagase, H and Jiang-Hua Mao and de Koning, J P and Minami, T and Balmain, A} } @article {134, title = {Advanced-stage cervix cancer: rapid tumour growth rather than late diagnosis.}, journal = {Br J Cancer}, volume = {83}, year = {2000}, month = {2000 Sep}, pages = {566-8}, abstract = {

Either diagnostic delay or tumour biology are possible factors governing the degree of spread at diagnosis of cervical cancer. To try to identify the most important parameter contributing to advanced stage, the duration of symptoms were recorded from patients scheduled for radiotherapy (n = 141) or radical hysterectomy (n = 36). In 146 cases tumour proliferation rates were evaluated following in vivo labelling with the DNA precursor BrdUrd. For symptomatic patients there was no association between duration of symptoms and stage at presentation. There was a significant trend for patients with increasing tumour stage to have more rapidly proliferating tumours with higher mean labelling index (LI) measurements (P = 0.001) and a shorter mean potential doubling time (Tpot) (P = 0.023). Socio economic deprivation may be associated with shorter Tpot values. The conclusion from this data is that stage at diagnosis is more dependent on the biological behaviour of the tumour, as expressed by proliferation rates, than delay in presentation.

}, keywords = {Adult, Aged, Biopsy, Bromodeoxyuridine, DNA, Female, Flow Cytometry, Humans, Middle Aged, Ploidies, Time Factors, Uterine Cervical Neoplasms, Vaginal Smears}, issn = {0007-0920}, doi = {10.1054/bjoc.2000.1336}, author = {Symonds, P and Bolger, B and Hole, D and Jiang-Hua Mao and Cooke, T} } @article {132, title = {Apoptosis in cervical squamous carcinoma: predictive value for survival following radiotherapy.}, journal = {J Clin Pathol}, volume = {53}, year = {2000}, month = {2000 Mar}, pages = {197-200}, abstract = {

BACKGROUND: Apoptosis, or programmed cell death, can be induced by radiotherapy. The extent of apoptosis in a tumour before treatment may have important implications for response to radiotherapy and long term survival.

AIM: To examine the extent of apoptosis in tumour tissue from patients with squamous carcinoma of the cervix before radiotherapy, and to correlate this with response to treatment and prognosis.

METHODS: The percentage of apoptotic cells was assessed in 146 carcinomas of the cervix from patients scheduled to receive radiotherapy. The CAS 200 static image analysis system was used to count the number of tumour nuclei per high power field, while the numbers of apoptotic cells in the same field were visualised simultaneously on the image analyser and recorded manually.

RESULTS: The median apoptotic level was 0.73\%. Patients were divided into two groups around the median. There was no statistically significant difference in outcome between the two groups as determined by long term survival following radiotherapy.

CONCLUSIONS: The CAS 200 static image analyser system can be used to assist in the rapid semiautomated assessment of apoptosis in conventionally prepared tissue. The results suggest that the apoptotic state of a tumour before treatment is of no value in predicting response to radiotherapy and subsequent prognosis. Tumour stage, size, and BrdU labelling index, as a measure of proliferation rate, remain the most important prognostic factors in terms of predicting local tumour control.

}, keywords = {Analysis of Variance, Apoptosis, Carcinoma, Squamous Cell, Female, Humans, Predictive Value of Tests, Survival Rate, Uterine Cervical Neoplasms}, issn = {0021-9746}, author = {Paxton, J R and Bolger, B S and Armour, A and Symonds, R P and Jiang-Hua Mao and Burnett, R A} } @article {133, title = {Factors affecting fetal weight distribution in women with type I diabetes.}, journal = {BJOG}, volume = {107}, year = {2000}, month = {2000 Aug}, pages = {1001-6}, abstract = {

OBJECTIVE: To identify factors independently affecting fetal weight in women with type I diabetes.

DESIGN: Prospectively recorded data in consecutive women with type I diabetes, between 1975-1992.

SETTING: Simpson Memorial Maternity Hospital, Edinburgh. Population Three hundred and two pregnancies with type I diabetes identified before pregnancy, with antenatal care and delivery in the Simpson Memorial Maternity Hospital, a singleton pregnancy, and the same diabetic physician.

METHODS: Normal ranges for birthweight were established for the total hospital population. All cases and the total population had pregnancy dating by ultrasound. The relation between standardised birthweight and explanatory variables was investigated using correlation analysis, t tests and chi2 tests as appropriate, and subsequently using multiple linear regression.

RESULTS: Standardised birthweight in cases, compared with the reference population, showed a unimodal, approximately normal distribution, markedly shifted to the right (mean + 1.26 SD). The most predictive variable was glycated haemoglobin concentration at 27-33 weeks, which explained 6.3\% of the birthweight variance, while smoking explained 2.7\% and maternal weight 2.0\%. There was a trend towards a negative relationship with glycated haemoglobin concentration at 6-12 weeks. Smoking and glycated haemoglobin concentration were strongly intercorrelated.

CONCLUSIONS: Most of the variance in standardised birthweight remains unexplained, but glycated haemoglobin concentration at 27-33 weeks is the most powerful explanatory variable. Possible reasons why there is not a stronger relationship between markers of maternal glycaemia and birthweight are discussed.

}, keywords = {Birth Weight, Diabetes Mellitus, Type 1, Female, Fetal Weight, Hemoglobin A, Glycosylated, Hemoglobinuria, Humans, Hypoglycemia, Infant, Newborn, Pregnancy, Pregnancy in Diabetics, Prospective Studies, Risk Factors, Scotland, Smoking}, issn = {1470-0328}, author = {Johnstone, F D and Jiang-Hua Mao and Steel, J M and Prescott, R J and Hume, R} } @article {130, title = {LD78beta, a non-allelic variant of human MIP-1alpha (LD78alpha), has enhanced receptor interactions and potent HIV suppressive activity.}, journal = {J Biol Chem}, volume = {274}, year = {1999}, month = {1999 Jun 18}, pages = {17478-83}, abstract = {

Chemokines play diverse roles in inflammatory and non-inflammatory situations via activation of heptahelical G-protein-coupled receptors. Also, many chemokine receptors can act as cofactors for cellular entry of human immunodeficiency virus (HIV) in vitro. CCR5, a receptor for chemokines MIP-1alpha (LD78alpha), MIP-1beta, RANTES, and MCP2, is of particular importance in vivo as polymorphisms in this gene affect HIV infection and rate of progression to AIDS. Moreover, the CCR5 ligands can prevent HIV entry through this receptor and likely contribute to the control of HIV infection. Here we show that a non-allelic isoform of human MIP-1alpha (LD78alpha), termed LD78beta or MIP-1alphaP, has enhanced receptor binding affinities to CCR5 (approximately 6-fold) and the promiscuous beta-chemokine receptor, D6 (approximately 15-20-fold). We demonstrate that a proline residue at position 2 of MIP-1alphaP is responsible for this enhanced activity. Moreover, MIP-1alphaP is by far the most potent natural CCR5 agonist described to date, and importantly, displays markedly higher HIV1 suppressive activity than all other human MIP-1alpha isoforms examined. In addition, while RANTES has been described as the most potent inhibitor of CCR5-mediated HIV entry, MIP-1alphaP was as potent as, if not more potent than, RANTES in HIV-1 suppressive assays. This property suggests that MIP-1alphaP may be of importance in controlling viral spread in HIV-infected individuals.

}, keywords = {Amino Acid Sequence, Animals, Anti-HIV Agents, Cell Line, Chemokine CCL3, Chemokine CCL4, Chemokine CCL5, HIV-1, Humans, Macrophage Inflammatory Proteins, Mice, Molecular Sequence Data, Protein Binding, Receptors, CCR1, Receptors, CCR10, Receptors, CCR5, Receptors, Chemokine}, issn = {0021-9258}, author = {Nibbs, R J and Yang, J and Landau, N R and Jiang-Hua Mao and Graham, G J} } @article {131, title = {A subset of skin tumor modifier loci determines survival time of tumor-bearing mice.}, journal = {Proc Natl Acad Sci U S A}, volume = {96}, year = {1999}, month = {1999 Dec 21}, pages = {15032-7}, abstract = {

Studies of mouse models of human cancer have established the existence of multiple tumor modifiers that influence parameters of cancer susceptibility such as tumor multiplicity, tumor size, or the probability of malignant progression. We have carried out an analysis of skin tumor susceptibility in interspecific Mus musculus/Mus spretus hybrid mice and have identified another seven loci showing either significant (six loci) or suggestive (one locus) linkage to tumor susceptibility or resistance. A specific search was carried out for skin tumor modifier loci associated with time of survival after development of a malignant tumor. A combination of resistance alleles at three markers [D6Mit15 (Skts12), D7Mit12 (Skts2), and D17Mit7 (Skts10)], all of which are close to or the same as loci associated with carcinoma incidence and/or papilloma multiplicity, is significantly associated with increased survival of mice with carcinomas, whereas the reverse combination of susceptibility alleles is significantly linked to early mortality caused by rapid carcinoma growth (chi(2) = 25.22; P = 5.1 x 10(-8)). These data indicate that host genetic factors may be used to predict carcinoma growth rate and/or survival of individual backcross mice exposed to the same carcinogenic stimulus and suggest that mouse models may provide an approach to the identification of genetic modifiers of cancer survival in humans.

}, keywords = {Animals, Carcinoma, Chimera, Genetic Linkage, Genetic Markers, Genetic Predisposition to Disease, Mice, Muridae, Phenotype, Quantitative Trait, Heritable, Regression Analysis, Skin Neoplasms, Species Specificity, Survival Analysis}, issn = {0027-8424}, author = {Nagase, H and Jiang-Hua Mao and Balmain, A} } @article {129, title = {Stochastic modelling of tumorigenesis in p53 deficient mice.}, journal = {Br J Cancer}, volume = {77}, year = {1998}, month = {1998}, pages = {243-52}, abstract = {

Stochastic models of tumorigenesis have been developed to investigate the implications of experimental data on tumour induction in wild-type and p53-deficient mice for tumorigenesis mechanisms. Conventional multistage models in which inactivation of each p53 allele represents a distinct stage predict excessively large numbers of tumours in p53-deficient genotypes, allowing this category of model to be rejected. Multistage multipath models, in which a p53-mediated pathway co-exists with one or more p53-independent pathways, are consistent with the data, although these models require unknown pathways and do not enable age-specific curves of tumour appearance to be computed. An alternative model that fits the data is the {\textquoteright}multigate{\textquoteright} model in which tumorigenesis results from a small number of gate-pass (enabling) events independently of p53 status. The role of p53 inactivation is as a rate modifier that accelerates the gate-pass events. This model implies that wild-type p53 acts as a {\textquoteright}caretaker{\textquoteright} to maintain genetic uniformity in cell populations, and that p53 inactivation increases the probability of occurrence of a viable cellular mutant by a factor of about ten. The multigate model predicts a relationship between the time pattern of tumour occurrence and tumour genotype that should be experimentally testable. Stochastic modelling may help to distinguish {\textquoteright}gatekeeper{\textquoteright} and {\textquoteright}caretaker{\textquoteright} genes in other tumorigenic pathays.

}, keywords = {Animals, Gene Deletion, Genes, p53, Mathematics, Mice, Mice, Knockout, Models, Biological, Mutation, Neoplasms, Experimental, Neoplastic Stem Cells, Stochastic Processes}, issn = {0007-0920}, author = {Jiang-Hua Mao and Lindsay, K A and Balmain, A and Wheldon, T E} } @article {128, title = {A two-stage model for childhood acute lymphoblastic leukemia: application to hereditary and nonhereditary leukemogenesis.}, journal = {Math Biosci}, volume = {139}, year = {1997}, month = {1997 Jan 1}, pages = {1-24}, abstract = {

A differential equation model is developed to represent a two-stage mutational process leading to childhood acute lymphoblastic leukemia (ALL). Leukemogenesis is modeled as transformation of target stem cells that initially grow rapidly in the embryo but plateau and then decline in postnatal childhood. Inheritance of the first of two leukemogenic mutations is allowed as a possibility in a small minority of leukemic patients who would characteristically develop leukemia at an early age. The model is shown to be capable of providing good fits to incidence data for childhood ALL; these fits allow estimation of some parameters of the model. The analysis shows that individuals inheriting one of the two mutations necessary for ALL would be likely to experience "multiclonal leukemogenesis"; that is, the parallel development of several leukemic clones arising from multiple independent leukemic events. The model suggests that between two and ten such clones would typically have developed in such individuals by the time of diagnosis. The main conclusions of the deterministic investigation were confirmed by stochastic modeling. The existence of multiclonal leukemogenesis is in principle testable by molecular biological methods (clonality analysis) that rely on the random inactivation of one of two X-chromosomes in normal female subjects. It is expected that the mathematical methods developed here will also be useful for more general (N-stage) models of malignant transformation of stem cell populations undergoing growth or decline.

}, keywords = {Aging, Child, Child, Preschool, Embryo, Mammalian, Female, Humans, Incidence, Male, Middle Aged, Models, Genetic, Models, Theoretical, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Sex Factors, Stochastic Processes}, issn = {0025-5564}, author = {Wheldon, E G and Lindsay, K A and Wheldon, T E and Jiang-Hua Mao} } @article {126, title = {Clinical and ultrasound prediction of macrosomia in diabetic pregnancy.}, journal = {Br J Obstet Gynaecol}, volume = {103}, year = {1996}, month = {1996 Aug}, pages = {747-54}, abstract = {

OBJECTIVE: To study prospectively the prediction power, at different gestations, of clinical and ultrasound measurements for fetal size in diabetic pregnancy.

SETTING: A large combined obstetric diabetic clinic in a teaching hospital.

PARTICIPANTS: One hundred and eighty-one pregnancies in which women had scans at least two of three specific time points and who were delivered of singletons after 34 weeks: 73\% were pre-gestational insulin-dependent diabetics, the others were pre-gestational White class A or gestational diabetics.

INTERVENTIONS: Clinical estimates of fundal height and fetal size and ultrasound estimates of abdominal circumference and head circumference were routinely carried out at gestational ages of 28, 34 and 38 weeks or before delivery.

MAIN OUTCOME MEASURES: Standardised birthweight, corrected for gestation and parity. The relation with clinical and ultrasound measurements was investigated using multiple linear regression and the capability of the measurements to predict macrosomic births (> 95th centile of normals) using receiver-operator characteristic curves.

RESULTS: All measurements are poor predictors of eventual standardised birthweight. Prediction improves with closeness to delivery. Prediction is significantly improved by adding ultrasound to clinical information, but at 34 weeks or later this only contributes 8\% of the variance. There is no difference in the prediction power for macrosomia between clinical and ultrasound measurements.

CONCLUSIONS: Even regular serial scanning and clinical examination will not always diagnose the macrosomic fetus in diabetic pregnancy. In our hands, clinical examination is as predictive as ultrasound measurements. Ultrasound does add to clinical prediction power but only to a small extent. Ultrasound should be used in a selected way, as defined by clinical findings, and with recognition and understanding of the errors and biases involved.

}, keywords = {Birth Weight, Diabetes, Gestational, Female, Fetal Macrosomia, Forecasting, Gestational Age, Humans, Parity, Pregnancy, Pregnancy in Diabetics, Prospective Studies, Sensitivity and Specificity, Ultrasonography, Prenatal}, issn = {0306-5456}, author = {Johnstone, F D and Prescott, R J and Steel, J M and Jiang-Hua Mao and Chambers, S and Muir, N} } @article {124, title = {An open, prospective comparison of beta 2 agonists given via nebuliser, Nebuhaler, or pressurised inhaler by ambulance crew as emergency treatment.}, journal = {Thorax}, volume = {50}, year = {1995}, month = {1995 Jan}, pages = {79-80}, abstract = {

BACKGROUND: The merits of the use of beta 2 agonists by ambulance crew and best methods of delivery have not been fully explored.

METHODS: A prospective comparison has been made of treatments applied in three districts in South Wales (200 micrograms salbutamol by pressurised inhaler, 5 mg salbutamol via nebuliser, and 5 mg terbutaline via Nebuhaler) by emergency ambulance personnel to acutely wheezy patients en route to hospital. Pulse rate, respiratory rate, peak expiratory flow rate (PEFR), and breathlessness scored on a visual analogue scale were compared before and after treatment. Data were collected on diagnosis, artificial ventilation, cardiorespiratory arrest, and death.

RESULTS: Thirty eight patients received salbutamol inhaler, 51 salbutamol via nebuliser, and 41 terbutaline via Nebuhaler. There were greater reductions in respiratory rate and breathlessness score and more improvement in PEFR in the group receiving nebulised salbutamol than in the other two groups. No patient was ventilated and of the five deaths none was caused by asthma.

CONCLUSIONS: For wheezy, breathless patients treated en route to hospital by emergency ambulance personnel, 5 mg salbutamol given by an oxygen-driven nebuliser was more effective than either 5 mg terbutaline via a Nebuhaler or 200 micrograms salbutamol via a pressurised inhaler.

}, keywords = {Acute Disease, Administration, Inhalation, Adolescent, Adult, Aged, Albuterol, Analysis of Variance, Emergencies, Emergency Medical Services, Female, Humans, Male, Middle Aged, Nebulizers and Vaporizers, Prospective Studies, Respiratory Sounds, Terbutaline, Wales}, issn = {0040-6376}, author = {Campbell, I A and Colman, S B and Jiang-Hua Mao and Prescott, R J and Weston, C F} } @article {125, title = {A stochastic model for multistage tumorigenesis in developing and adult mice.}, journal = {Math Biosci}, volume = {129}, year = {1995}, month = {1995 Oct}, pages = {95-110}, abstract = {

A stochastic process model for one-, two-, and three-stage malignant transformation has been developed for embryonic and adult mice. The model has been used to study the influence of mutation rate, number of stages required for transformation, and number of stem cells at risk on the kinetics of spontaneous appearance of malignant tumors. As expected, tumors appeared earlier with fewer required mutational stages, higher mutation rate, and greater number of stem cells at risk. However, a notable observation was that tumor latency was more strongly influenced by number of stages and by stem cell number at lower mutation rates than at higher rates. This implies that tumor latency may be a less useful observation when the spontaneous mutation rate is high. In the future, the model will be applied to analysis of tumorigenesis experiments in transgenic mice with p53 genetic abnormalities, subjected to irradiation or chemical tumorigenesis at different stages of development.

}, keywords = {Animals, Cell Differentiation, Cell Division, Cell Transformation, Neoplastic, Computer Simulation, Embryo, Mammalian, Kinetics, Mice, Models, Biological, Stem Cells, Stochastic Processes}, issn = {0025-5564}, author = {Jiang-Hua Mao and Wheldon, T E} } @article {122, title = {Insulin requirements during pregnancy in women with type I diabetes.}, journal = {Obstet Gynecol}, volume = {83}, year = {1994}, month = {1994 Feb}, pages = {253-8}, abstract = {

OBJECTIVES: To document individual variations in the rise in insulin requirements during type I diabetic pregnancies, to relate the degree of increase to maternal characteristics and fetal outcome, and to examine these factors in a subgroup of patients experiencing a large fall in insulin requirement in the third trimester.

METHODS: Insulin dose was documented in 237 pregnancies in women with type I diabetes. Multiple regression analysis was performed to identify significant associations with maternal and fetal characteristics. Eighteen pregnancies with a fall in insulin requirement of 30\% or more in the third trimester were considered in detail.

RESULTS: The mean absolute increase in insulin requirement was 52 units. The degree of rise was significantly related to maternal weight gain between 20-29 weeks and maternal weight at booking, and was inversely related to duration of diabetes. It was not related to the degree of diabetes control, complications of pregnancy, White class, or outcome of pregnancy. In the 18 women experiencing a large fall in insulin requirement, there was no relation with maternal characteristics or fetal outcome.

CONCLUSION: There is a wide individual variation in the change in insulin requirements in type I diabetic pregnancy. The degree of increase is related only to maternal weight gain during weeks 20-29 and maternal weight at booking, and is inversely related to duration of diabetes. Large falls in insulin requirement remain unexplained and may not be associated with placental failure.

}, keywords = {Diabetes Mellitus, Type 1, Female, Humans, Insulin, Pregnancy, Pregnancy in Diabetics, Pregnancy Outcome, Pregnancy Trimester, Third, Regression Analysis, Weight Gain}, issn = {0029-7844}, author = {Steel, J M and Johnstone, F D and Hume, R and Jiang-Hua Mao} } @article {123, title = {Urethral stricture and urethritis in men in Scotland.}, journal = {Genitourin Med}, volume = {70}, year = {1994}, month = {1994 Dec}, pages = {403-5}, abstract = {

OBJECTIVES: To examine the incidence of urethral stricture in men in Scotland during the years 1982-1991 in relation to the changing incidence of gonococcal and non-gonococcal urethritis (NGU) over the past 20 years.

DESIGN: Retrospective study of incidence of urethral stricture in Scotland.

METHOD: The number of new men in whom a diagnosis of urethral stricture was made for the years 1982-1991 was obtained using the new Scottish Record Linkage system, and the number of cases of gonorrhoea and NGU was obtained from Communicable Diseases (Scotland) Unit. Age-specific rates of urethral stricture were calculated and the Poisson regression model was used to test if there was a trend of rate with age or time change.

RESULTS: There was a highly significant increase in the incidence of urethral stricture with age but only a slight increase in incidence over the study period within each age group.

CONCLUSION: As the interaction between age and time was not significant, it is concluded that urethritis associated with sexually transmitted organisms is an uncommon cause of urethral stricture in Scotland.

}, keywords = {Adolescent, Adult, Age Factors, Aged, Chlamydia Infections, Gonorrhea, Humans, Incidence, Male, Middle Aged, Regression Analysis, Retrospective Studies, Scotland, Time Factors, Urethral Stricture, Urethritis}, issn = {0266-4348}, author = {McMillan, A and Pakianathan, M and Jiang-Hua Mao and Macintyre, C C} } @article {119, title = {Identification of prognostic groups in follicular lymphoma. The Scotland and Newcastle Lymphoma Group Therapy Working Party.}, journal = {Leuk Lymphoma}, volume = {10}, year = {1993}, month = {1993 May}, pages = {89-99}, abstract = {

Follicular lymphoma is often seen as an indolent disease with a reasonable medium-term survival. We have used the information in the Scotland and Newcastle Lymphoma Group database to devise an index which is easily calculated and differentiates patients into poor, intermediate and good prognostic groups with 5 years survivals of 24\%, 61\% and 86\% respectively. The key factors at presentation are age, ECOG performance status, stage and the presence or absence of B symptoms or gastro-intestinal tract involvement. The use of such an index permits early identification of patients with a poor prognosis for whom more intensive treatment could be offered.

}, keywords = {Adult, Age Factors, Aged, Female, Humans, Lymphoma, Follicular, Male, Middle Aged, Prognosis, Survival Rate}, issn = {1042-8194}, doi = {10.3109/10428199309147361}, author = {Cameron, D A and Leonard, R C and Jiang-Hua Mao and Prescott, R J} } @article {121, title = {Macrophage prostaglandin E2 and oxidative responses to endotoxin during immunosuppression associated with anaesthesia and transfusion.}, journal = {Prostaglandins Leukot Essent Fatty Acids}, volume = {49}, year = {1993}, month = {1993 Dec}, pages = {945-53}, abstract = {

The widespread use of blood transfusion in major surgical procedures has led to concern about the immunosuppressive effect of transfusion on patients with underlying malignancy. Transfusion may also suppress the host response to infection. The cellular mechanisms of transfusion-associated immunosuppression may involve macrophage prostaglandin E2 (PGE2) in modulating the host response to cancer and infection. We previously observed that the transfusion of blood increased PGE2 production by unstimulated macrophages. To investigate this PGE2 associated immunosuppression, we studied the effect of transfusion of rats using a physiological stimulus of macrophage PGE2 production, bacterial endotoxin. In the same macrophages, we analysed intracellular oxidative activity. Both allogeneic and syngeneic blood transfusion were associated with increased PGE2 release by macrophages. This stimulation of PGE2 increased with duration of storage of blood. A similar effect of serum indicated that a humoral factor was involved. Endotoxin (50 ng/ml-500 micrograms/ml) stimulated PGE2 production in all transfused subjects. The lowest endotoxin concentration gave proportionately the greatest stimulation. Oxidative activity was down-regulated in macrophages of transfused rats, supporting an immunosuppressive role of PGE2 within the macrophage. An effect of surgery on the oxidative response was also detected.

}, keywords = {Anesthesia, Animals, Blood Transfusion, Dinoprostone, Dose-Response Relationship, Drug, Endotoxins, Immune Tolerance, Macrophages, Peritoneal, Male, Oxidation-Reduction, Rats, Rats, Inbred Lew, Superoxides}, issn = {0952-3278}, author = {Ross, W B and Leaver, H A and Yap, P L and Raab, G M and Su, B H and Carter, D C and Jiang-Hua Mao and Qian, W and Prescott, R J} } @article {120, title = {Successful application of a previously derived prognostic index in the analysis of a randomised trial of 281 patients with high grade non-Hodgkin{\textquoteright}s lymphoma (HIGNHL).}, journal = {Ann Oncol}, volume = {4}, year = {1993}, month = {1993 Dec}, pages = {853-6}, abstract = {

BACKGROUND: The selection of patients for experimental therapies for high grade non-Hodgkin{\textquoteright}s lymphoma (NHL) is now recognised to be very influential in affecting results. We showed previously that simple clinical indices could be used to create an index of risk of death in a series of 972 patients. We wished to test this prognostic index in a subsequent randomised treatment trial of CHOP-based chemotherapy.

PATIENTS AND METHODS: 281 patients with high grade NHL randomised between two chemotherapy designs were followed up from 1-6 years and survival analysed to develop a Cox model which was then compared against the previously described prognostic index.

RESULTS: The previous index based on age, sex, performance status, stage and symptoms was similar to the data-derived model. Three year survivals for the best (109), intermediate (93) and worst (79) cohorts were 69\%, 50\% and 24\% respectively, similar to the survivals in the previous series.

CONCLUSIONS: CHOP-based chemotherapy is probably adequate for around 40\% of cases of high grade NHL. The prospective test of a prognostic index shows that we can be confident about selecting poor-risk patients for trials of novel therapies, including dose intensification.

}, keywords = {Aged, Antineoplastic Combined Chemotherapy Protocols, Bleomycin, Cyclophosphamide, Doxorubicin, Humans, Lymphoma, Non-Hodgkin, Methotrexate, Middle Aged, Prednisone, Prognosis, Prospective Studies, Survival Analysis, Vincristine}, issn = {0923-7534}, author = {Leonard, R C and Prescott, R J and Jiang-Hua Mao and White, J M} }