@article {284, title = {Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.}, journal = {Mol Cell}, volume = {61}, year = {2016}, month = {2016 Feb 18}, pages = {535-46}, abstract = {

XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging.

}, keywords = {Animals, BRCA1 Protein, BRCA2 Protein, Cell Line, Tumor, Cockayne Syndrome, DNA Repair, DNA-Binding Proteins, Endonucleases, Genome, Human, Genomic Instability, HeLa Cells, Homologous Recombination, Humans, Mice, Nuclear Proteins, Phosphorylation, Rad51 Recombinase, Transcription Factors, Tumor Suppressor Proteins}, issn = {1097-4164}, doi = {10.1016/j.molcel.2015.12.026}, author = {Trego, Kelly S and Groesser, Torsten and Davalos, Albert R and Parplys, Ann C and Zhao, Weixing and Nelson, Michael R and Hlaing, Ayesu and Shih, Brian and Rydberg, Bjorn and Pluth, Janice M and Tsai, Miaw-Sheue and Hoeijmakers, Jan H J and Sung, Patrick and Wiese, Claudia and Campisi, Judith and Cooper, Priscilla K} } @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 {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 {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 {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 {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 {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 {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 {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 {281, title = {Nanosensor dosimetry of mouse blood proteins after exposure to ionizing radiation.}, journal = {Sci Rep}, volume = {3}, year = {2013}, month = {2013}, pages = {2234}, abstract = {

Giant magnetoresistive (GMR) nanosensors provide a novel approach for measuring protein concentrations in blood for medical diagnosis. Using an in vivo mouse radiation model, we developed protocols for measuring Flt3 ligand (Flt3lg) and serum amyloid A1 (Saa1) in small amounts of blood collected during the first week after X-ray exposures of sham, 0.1, 1, 2, 3, or 6 Gy. Flt3lg concentrations showed excellent dose discrimination at >= 1 Gy in the time window of 1 to 7 days after exposure except 1 Gy at day 7. Saa1 dose response was limited to the first two days after exposure. A multiplex assay with both proteins showed improved dose classification accuracy. Our magneto-nanosensor assay demonstrates the dose and time responses, low-dose sensitivity, small volume requirements, and rapid speed that have important advantages in radiation triage biodosimetry.

}, keywords = {Animals, Biomarkers, Biosensing Techniques, Blood Proteins, Dose-Response Relationship, Radiation, Female, Male, Membrane Proteins, Mice, Nanotechnology, Radiation, Ionizing, Radiometry, Reproducibility of Results, Serum Amyloid A Protein, Time Factors}, issn = {2045-2322}, doi = {10.1038/srep02234}, author = {Kim, Dokyoon and Marchetti, Francesco and Chen, Zuxiong and Zaric, Sasa and Wilson, Robert J and Hall, Drew A and Gaster, Richard S and Lee, Jung-Rok and Wang, Junyi and Osterfeld, Sebastian J and Yu, Heng and White, Robert M and Blakely, William F and Peterson, Leif E and Bhatnagar, Sandhya and Mannion, Brandon and Tseng, Serena and Roth, Kristen and Coleman, Matthew and A Snijders and Wyrobek, Andrew J and Wang, Shan X} } @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 {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 {82, title = {CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues}, journal = {Cancer Discov}, volume = {2}, year = {2012}, month = {2012 Sep}, pages = {826-39}, abstract = {

UNLABELLED: Although high mammographic density is considered one of the strongest risk factors for invasive breast cancer, the genes involved in modulating this clinical feature are unknown. Tissues of high mammographic density share key histologic features with stromal components within malignant lesions of tumor tissues, specifically low adipocyte and high extracellular matrix (ECM) content. We show that CD36, a transmembrane receptor that coordinately modulates multiple protumorigenic phenotypes, including adipocyte differentiation, angiogenesis, cell-ECM interactions, and immune signaling, is greatly repressed in multiple cell types of disease-free stroma associated with high mammographic density and tumor stroma. Using both in vitro and in vivo assays, we show that CD36 repression is necessary and sufficient to recapitulate the above-mentioned phenotypes observed in high mammographic density and tumor tissues. Consistent with a functional role for this coordinated program in tumorigenesis, we observe that clinical outcomes are strongly associated with CD36 expression.

SIGNIFICANCE: CD36 simultaneously controls adipocyte content and matrix accumulation and is coordinately repressed in multiple cell types within tumor and high mammographic density stroma, suggesting that activation of this stromal program is an early event in tumorigenesis. Levels of CD36 and extent of mammographic density are both modifiable factors that provide potential for intervention.

}, keywords = {Adipocytes, Animals, Antigens, CD36, Breast Neoplasms, Cell Differentiation, Female, Humans, Mammography, Mice, Mice, Knockout, Risk Factors, Signal Transduction, Stromal Cells}, issn = {2159-8290}, doi = {10.1158/2159-8290.CD-12-0107}, author = {DeFilippis, Rosa Anna and Hang Chang and Dumont, Nancy and Rabban, Joseph T and Chen, Yunn-Yi and Fontenay, Gerald V and Berman, Hal K and Gauthier, Mona L and Zhao, Jianxin and Hu, Donglei and Marx, James J and Tjoe, Judy A and Ziv, Elad and Febbraio, Maria and Kerlikowske, Karla and Parvin, Bahram and Tlsty, Thea D} } @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 {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 {83, title = {Identification of fluorescent compounds with non-specific binding property via high throughput live cell microscopy}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e28802}, abstract = {

INTRODUCTION: Compounds exhibiting low non-specific intracellular binding or non-stickiness are concomitant with rapid clearing and in high demand for live-cell imaging assays because they allow for intracellular receptor localization with a high signal/noise ratio. The non-stickiness property is particularly important for imaging intracellular receptors due to the equilibria involved.

METHOD: Three mammalian cell lines with diverse genetic backgrounds were used to screen a combinatorial fluorescence library via high throughput live cell microscopy for potential ligands with high in- and out-flux properties. The binding properties of ligands identified from the first screen were subsequently validated on plant root hair. A correlative analysis was then performed between each ligand and its corresponding physiochemical and structural properties.

RESULTS: The non-stickiness property of each ligand was quantified as a function of the temporal uptake and retention on a cell-by-cell basis. Our data shows that (i) mammalian systems can serve as a pre-screening tool for complex plant species that are not amenable to high-throughput imaging; (ii) retention and spatial localization of chemical compounds vary within and between each cell line; and (iii) the structural similarities of compounds can infer their non-specific binding properties.

CONCLUSION: We have validated a protocol for identifying chemical compounds with non-specific binding properties that is testable across diverse species. Further analysis reveals an overlap between the non-stickiness property and the structural similarity of compounds. The net result is a more robust screening assay for identifying desirable ligands that can be used to monitor intracellular localization. Several new applications of the screening protocol and results are also presented.

}, keywords = {Animals, Arabidopsis, Cell Line, Cell Survival, Combinatorial Chemistry Techniques, Fluorescent Dyes, Humans, Ligands, Mice, Microscopy, Small Molecule Libraries}, issn = {1932-6203}, doi = {10.1371/journal.pone.0028802}, author = {Nath, Sangeeta and Spencer, Virginia A and Ju Han and Hang Chang and Zhang, Kai and Fontenay, Gerald V and Anderson, Charles and Hyman, Joel M and Nilsen-Hamilton, Marit and Chang, Young-Tae and Parvin, Bahram} } @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 {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 {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 {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 {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 {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 {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 {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 {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 {300, title = {Antidepressant evaluation of polysaccharides from a Chinese herbal medicine Banxia-houpu decoction.}, journal = {Phytother Res}, volume = {18}, year = {2004}, month = {2004 Mar}, pages = {204-7}, abstract = {

Banxia-houpu decoction, a traditional Chinese medicine has been used in the treatment of depression. The present study confirmed that oral administration of polysaccharides from Banxia-houpu decoction, exhibited a reduction in the immobility time in the tail suspension and in the forced swimming tests in mice in a time-dependent manner. This effect at a dose of 320 mg/kg was more potent than that at a dose of 640 mg/kg. The polysaccharides from Banxia-houpu decoction were active in animal models of depression with comparable effects to known antidepressants. The oral administration of the polysaccharides at a low dose for 4 weeks resulted in a significant increase in the monoamine neurotransmitter 5-hydroxytryptamine (5-HT) and dopamine (DA) levels in whole mouse brain, but produced no significant increase in 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) concentrations. The effect of polysaccharides on the brain neurotransmitter levels appeared to be quite different from the effect of fluoxetine, a serotonin specific reuptake inhibitor. The results indicate that the mode of action of polysaccharides from Banxia-houpu decoction in depression might be related to both 5-HT and DA systems.

}, keywords = {Animals, Antidepressive Agents, Behavior, Animal, Brain, Dopamine, Dose-Response Relationship, Drug, Drugs, Chinese Herbal, Male, Mice, Mice, Inbred ICR, Phytotherapy, Plant Extracts, Plants, Medicinal, Polysaccharides, Serotonin, Stress Disorders, Traumatic, Swimming}, issn = {0951-418X}, doi = {10.1002/ptr.1394}, author = {Yusong Guo and Kong, Lingdong and Wang, Yemin and Huang, Zhiqi} } @article {301, title = {A Chinese herbal medicine Ermiao wan reduces serum uric acid level and inhibits liver xanthine dehydrogenase and xanthine oxidase in mice.}, journal = {J Ethnopharmacol}, volume = {93}, year = {2004}, month = {2004 Aug}, pages = {325-30}, abstract = {

Ermiao wan, which is composed of phellodendri cortex and atractylodis rhizome, is described as eliminating heat, excreting dampness and anti-edema prescription in traditional Chinese medical literatures including Danxi{\textquoteright}s Experiences in Medicine and State Pharmacopoeia of People{\textquoteright}s Republic of China. So it is being used clinically in the treatment of gout and hyperuricemia in China. In the present study, the water extracts of Ermiao wan and phellodendri cortex at 840 and 480 mg/kg/day orally for 7 days were demonstrated to possess in vivo potent hypouricemic effects both in hyperuricemic mice pretreated with oxonate and in normal mice, respectively. In the hyperuricemic animals, the effect of Ermiao wan was equal to that of the reference drug allopurinol (at 10 mg/kg/day orally for 7 days), but in the normal mice, the former was weaker than latter. In addition, both Ermiao wan and phellodendri cortex were found to have in vivo relatively inhibitory effects on mouse liver xanthine dehydrogenase (XDH) and xanthine oxidase (XO) activities at the same dose described above. These inhibitory effects were weaker than that observed for allopurinol. Atractylodis rhizome at 340 mg/kg/day orally for 7 days did not show any effects on the above experiments. These results suggested that atractylodis rhizomes assisted and enhanced the effect of phellodendri cortex on reduction of serum uric acid level in hyperuricemic mice, and hypouricemic effects of Ermiao wan and phellodendri cortex may be achieved by other mechanism partly instead of the XDH and XO inhibition.

}, keywords = {Administration, Oral, Animals, Dose-Response Relationship, Drug, Drugs, Chinese Herbal, Enzyme Inhibitors, Hyperuricemia, Liver, Male, Mice, Mice, Inbred ICR, Phytotherapy, Plant Bark, Plant Extracts, Plants, Medicinal, Rhizome, Uric Acid, Xanthine Dehydrogenase, Xanthine Oxidase}, issn = {0378-8741}, doi = {10.1016/j.jep.2004.04.008}, author = {Kong, Ling Dong and Yang, Chen and Ge, Fei and Wang, Hai Dong and Yusong Guo} } @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 {302, title = {[Effects of aqueous extract in herba of Lysimachia christinae on hyperuricemia in mice].}, journal = {Zhongguo Zhong Yao Za Zhi}, volume = {27}, year = {2002}, month = {2002 Dec}, pages = {939-41, 944}, abstract = {

OBJECTIVE: To study hypouricemic effect of aqueous extract of Lysimachia christinae on hyperuricemia in mice.

METHOD: The uricase inhibitor potassium oxonate was used to induce hyperuricemia in mice, and serum uric acid level was determined with the phosphotungstic acid method.

RESULT: The aqueous extract of Lysimachia christinae, when administered orally to the oxonate-induced hyperuricemic mice at the doses of 5.2, 10.4 and 20.8 g.kg-1, was able to elicit dose-dependent hypouricemic effects. At these doses of the extract, the serum urate levels of the oxonate-pretreated mice showed no difference from the normal mice. In normal mice, however, oral administration of the extract at the same doses did not produce any observable hypouricemic effects.

CONCLUSION: The aqueous extract of Lysimachia christinae possesses potent hypuricemic effects on models of hyperuricemia in mice pretreated with oxonate.

}, keywords = {Animals, Drugs, Chinese Herbal, Female, Hyperuricemia, Mice, Plants, Medicinal, Primulaceae, Uric Acid}, issn = {1001-5302}, author = {Wang, Hai-dong and Ge, Fei and Yusong Guo and Kong, Ling-dong} } @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 {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 {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} }