@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 {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 {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 {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 {76, title = {Stress signaling from human mammary epithelial cells contributes to phenotypes of mammographic density}, journal = {Cancer Res}, volume = {74}, year = {2014}, month = {2014 Sep 15}, pages = {5032-44}, abstract = {

Telomere malfunction and other types of DNA damage induce an activin A-dependent stress response in mortal nontumorigenic human mammary epithelial cells that subsequently induces desmoplastic-like phenotypes in neighboring fibroblasts. Some characteristics of this fibroblast/stromal response, such as reduced adipocytes and increased extracellular matrix content, are observed not only in tumor tissues but also in disease-free breast tissues at high risk for developing cancer, especially high mammographic density tissues. We found that these phenotypes are induced by repression of the fatty acid translocase CD36, which is seen in desmoplastic and disease-free high mammographic density tissues. In this study, we show that epithelial cells from high mammographic density tissues have more DNA damage signaling, shorter telomeres, increased activin A secretion and an altered DNA damage response compared with epithelial cells from low mammographic density tissues. Strikingly, both telomere malfunction and activin A expression in epithelial cells can repress CD36 expression in adjacent fibroblasts. These results provide new insights into how high mammographic density arises and why it is associated with breast cancer risk, with implications for the definition of novel invention targets (e.g., activin A and CD36) to prevent breast cancer.

}, keywords = {Antigens, CD36, Breast Neoplasms, DNA Damage, Epithelial Cells, Female, Humans, Mammary Glands, Human, Phenotype, Signal Transduction}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-13-3390}, author = {DeFilippis, Rosa Anna and Fordyce, Colleen and Patten, Kelley and Hang Chang and Zhao, Jianxin and Fontenay, Gerald V and Kerlikowske, Karla and Parvin, Bahram and Tlsty, Thea D} } @article {202, title = {C2ORF40 suppresses breast cancer cell proliferation and invasion through modulating expression of M phase cell cycle genes.}, journal = {Epigenetics}, volume = {8}, year = {2013}, month = {2013 Jun}, pages = {571-83}, abstract = {

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

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

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

}, keywords = {Apoptosis, Breast Neoplasms, Cell Cycle Proteins, Cell Growth Processes, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, Down-Regulation, Epithelial-Mesenchymal Transition, F-Box Proteins, Genes, Tumor Suppressor, Humans, Microtubule-Associated Proteins, Prognosis, Transfection, Ubiquitin-Protein Ligases}, issn = {1949-2553}, doi = {10.18632/oncotarget.1581}, author = {Wang, Zeran and Liu, Yueyong and Zhang, Pengju and Zhang, Weiguo and Wang, Weijing and Curr, Kenneth and Wei, Guangwei and Jiang-Hua Mao} } @article {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 {77, title = {NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals}, journal = {Oncotarget}, volume = {4}, year = {2013}, month = {2013 Nov}, pages = {2010-20}, abstract = {

The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. However, the factors that prevent integration of signaling pathways that merge form and function are still largely unknown. We have identified nuclear factor kappa B (NFkB) as a transcriptional regulator that disrupts important microenvironmental cues necessary for tissue organization. We compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant S1 cells that form polarized spheres ({\textquoteright}acini{\textquoteright}), the malignant T4-2 cells that form large tumor-like clusters, and the {\textquoteright}phenotypically reverted{\textquoteright} T4-2 cells that polarize as a result of correction of the microenvironmental signaling. We identified 180 genes that display an increased expression in disorganized compared to polarized structures. Network, GSEA and transcription factor binding site analyses suggested that NFkB is a common activator for the 180 genes. NFkB was found to be activated in disorganized breast cancer cells, and inhibition of microenvironmental signaling via EGFR, beta1 integrin, MMPs, or their downstream signals suppressed its activation. The postulated role of NFkB was experimentally verified: Blocking the NFkB pathway with a specific chemical inhibitor or shRNA induced polarization and inhibited invasion of breast cancer cells in 3D cultures. These results may explain why NFkB holds promise as a target for therapeutic intervention: Its inhibition can reverse the oncogenic signaling involved in breast cancer progression and integrate the essential microenvironmental control of tissue architecture.

}, keywords = {Breast Neoplasms, Cell Line, Tumor, Female, Gene Expression, Humans, Imaging, Three-Dimensional, Microarray Analysis, NF-kappa B, Phenotype, Signal Transduction, Transcriptional Activation, Tumor Microenvironment}, issn = {1949-2553}, doi = {10.18632/oncotarget.1451}, author = {Becker-Weimann, Sabine and Xiong, Gaofeng and Furuta, Saori and Ju Han and Kuhn, Irene and Akavia, Uri-David and Pe{\textquoteright}er, Dana and Bissell, Mina J and Xu, Ren} } @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 {175, title = {Gene transcriptional networks integrate microenvironmental signals in human breast cancer.}, journal = {Integr Biol (Camb)}, volume = {3}, year = {2011}, month = {2011 Apr}, pages = {368-74}, abstract = {

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

}, keywords = {Breast Neoplasms, Cadherins, Cytokines, Extracellular Matrix, Extracellular Matrix Proteins, Female, Gene Expression Profiling, Gene Regulatory Networks, Humans, Integrins, Intercellular Signaling Peptides and Proteins, Mammary Glands, Human, Oligonucleotide Array Sequence Analysis, Receptor, Platelet-Derived Growth Factor beta, Receptors, Cytokine, Transforming Growth Factor beta, Tumor Microenvironment}, issn = {1757-9708}, doi = {10.1039/c0ib00087f}, author = {Xu, Ren and Jiang-Hua Mao} } @article {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 {171, title = {Deletion of the PER3 gene on chromosome 1p36 in recurrent ER-positive breast cancer.}, journal = {J Clin Oncol}, volume = {28}, year = {2010}, month = {2010 Aug 10}, pages = {3770-8}, abstract = {

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

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

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

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

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

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

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

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

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

}, keywords = {Biomarkers, Tumor, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Disease-Free Survival, DNA-Binding Proteins, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Oligonucleotide Array Sequence Analysis, Predictive Value of Tests, Prognosis, RNA Interference, RNA, Messenger}, issn = {1465-542X}, doi = {10.1186/bcr2487}, author = {Hu, Zhi and Huang, Ge and Sadanandam, Anguraj and Gu, Shenda and Lenburg, Marc E and Pai, Melody and Bayani, Nora and Blakely, Eleanor A and Gray, Joe W and Jiang-Hua Mao} } @article {86, title = {Linking changes in epithelial morphogenesis to cancer mutations using computational modeling}, journal = {PLoS Comput Biol}, volume = {6}, year = {2010}, month = {2010}, abstract = {

Most tumors arise from epithelial tissues, such as mammary glands and lobules, and their initiation is associated with the disruption of a finely defined epithelial architecture. Progression from intraductal to invasive tumors is related to genetic mutations that occur at a subcellular level but manifest themselves as functional and morphological changes at the cellular and tissue scales, respectively. Elevated proliferation and loss of epithelial polarization are the two most noticeable changes in cell phenotypes during this process. As a result, many three-dimensional cultures of tumorigenic clones show highly aberrant morphologies when compared to regular epithelial monolayers enclosing the hollow lumen (acini). In order to shed light on phenotypic changes associated with tumor cells, we applied the bio-mechanical IBCell model of normal epithelial morphogenesis quantitatively matched to data acquired from the non-tumorigenic human mammary cell line, MCF10A. We then used a high-throughput simulation study to reveal how modifications in model parameters influence changes in the simulated architecture. Three parameters have been considered in our study, which define cell sensitivity to proliferative, apoptotic and cell-ECM adhesive cues. By mapping experimental morphologies of four MCF10A-derived cell lines carrying different oncogenic mutations onto the model parameter space, we identified changes in cellular processes potentially underlying structural modifications of these mutants. As a case study, we focused on MCF10A cells expressing an oncogenic mutant HER2-YVMA to quantitatively assess changes in cell doubling time, cell apoptotic rate, and cell sensitivity to ECM accumulation when compared to the parental non-tumorigenic cell line. By mapping in vitro mutant morphologies onto in silico ones we have generated a means of linking the morphological and molecular scales via computational modeling. Thus, IBCell in combination with 3D acini cultures can form a computational/experimental platform for suggesting the relationship between the histopathology of neoplastic lesions and their underlying molecular defects.

}, keywords = {Apoptosis, Breast Neoplasms, Cell Proliferation, Computer Simulation, Epithelium, Extracellular Matrix, Female, Humans, Mammary Glands, Human, Models, Biological, Morphogenesis, Mutation, Receptor, ErbB-2}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1000900}, author = {Rejniak, Katarzyna A and Wang, Shizhen E and Bryce, Nicole S and Hang Chang and Parvin, Bahram and Jourquin, Jerome and Estrada, Lourdes and Gray, Joe W and Arteaga, Carlos L and Weaver, Alissa M and Quaranta, Vito and Anderson, Alexander R A} } @article {87, title = {Molecular predictors of 3D morphogenesis by breast cancer cell lines in 3D culture}, journal = {PLoS Comput Biol}, volume = {6}, year = {2010}, month = {2010 Feb}, pages = {e1000684}, abstract = {

Correlative analysis of molecular markers with phenotypic signatures is the simplest model for hypothesis generation. In this paper, a panel of 24 breast cell lines was grown in 3D culture, their morphology was imaged through phase contrast microscopy, and computational methods were developed to segment and represent each colony at multiple dimensions. Subsequently, subpopulations from these morphological responses were identified through consensus clustering to reveal three clusters of round, grape-like, and stellate phenotypes. In some cases, cell lines with particular pathobiological phenotypes clustered together (e.g., ERBB2 amplified cell lines sharing the same morphometric properties as the grape-like phenotype). Next, associations with molecular features were realized through (i) differential analysis within each morphological cluster, and (ii) regression analysis across the entire panel of cell lines. In both cases, the dominant genes that are predictive of the morphological signatures were identified. Specifically, PPARgamma has been associated with the invasive stellate morphological phenotype, which corresponds to triple-negative pathobiology. PPARgamma has been validated through two supporting biological assays.

}, keywords = {Biomarkers, Tumor, Breast Neoplasms, Cell Culture Techniques, Cell Line, Tumor, Female, Gene Expression Profiling, Histocytochemistry, Humans, Image Processing, Computer-Assisted, Models, Biological, Phenotype, PPAR gamma, Receptor, ErbB-2, Reproducibility of Results}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1000684}, author = {Han, Ju and Chang, Hang and Giricz, Orsi and Lee, Genee Y and Baehner, Frederick L and Gray, Joe W and Bissell, Mina J and Kenny, Paraic A and Parvin, Bahram} } @article {277, title = {Genomic profiling by array comparative genomic hybridization reveals novel DNA copy number changes in breast phyllodes tumours.}, journal = {Cell Oncol}, volume = {31}, year = {2009}, month = {2009}, pages = {31-9}, abstract = {

Breast phyllodes tumour (PT) is a rare fibroepithelial tumour. The genetic alterations contributing to its tumorigenesis are largely unknown. To identify genomic regions involved in pathogenesis and progression of PTs we obtained genome-wide copy number profiles by array comparative genomic hybridization (CGH).DNA was isolated from fresh-frozen tissue samples. 11 PTs and 3 fibroadenomas, a frequently occurring fibroepithelial breast tumour, were analyzed. Arrays composed of 2464 genomic clones were used, providing a resolution of ~1.4 Mb across the genome. Each clone contains at least one STS for linkage to the human genome sequence.No copy number changes were detected in fibroadenomas. On the other hand, 10 of 11 PT (91\%) showed DNA copy number alterations. The mean number of chromosomal events in PT was 5.5 (range 0-16) per case. A mean of 2.0 gains (range 0-10) and 3.0 losses (range 0-9) was seen per case of PT. Three cases showed amplifications. DNA copy number change was not related to PT grade. We observed recurrent loss on chromosome 1q, 4p, 10, 13q, 15q, 16, 17p, 19 and X. Recurrent copy number gain was seen on 1q, 2p, 3q, 7p, 8q, 16q, 20.In this study we used array CGH for genomic profiling of fibroepithelial breast tumours. Whereas most PT showed chromosomal instability, fibroadenomas lacked copy number changes. Some copy number aberrations had not previously been associated with PT. Several well-known cancer related genes, such as TP53 and members of the Cadherin, reside within the recurrent regions of copy number alteration. Since copy number change was found in all benign PT, genomic instability may be an early event in PT genesis.

}, keywords = {Breast Neoplasms, Chromosomes, Human, Comparative Genomic Hybridization, Female, Gene Dosage, Gene Expression Profiling, Genome, Human, Humans, Oligonucleotide Array Sequence Analysis, Phyllodes Tumor}, issn = {1875-8606}, author = {Kuijper, Arno and A Snijders and Berns, Els M J J and Kuenen-Boumeester, Vibeke and van der Wall, Elsken and Albertson, Donna G and van Diest, Paul J} } @article {273, title = {FBXW7 and DNA copy number instability.}, journal = {Breast Cancer Res Treat}, volume = {109}, year = {2008}, month = {2008 May}, pages = {47-54}, abstract = {

SKP1-cullin-F-box protein (SCF) type ubiquitin ligases degrade proteins controlling the G1/S transition. Deficiency for FBXW7 (also known as hCDC4), which encodes the F-box protein of the SCF type ubiquitin ligase is associated with genomic instability. Here, we investigated the association of FBXW7 deficiency with chromosomal instability in breast cancer. We screened 49 tumors previously profiled by array CGH for mutations in conserved regions of FBXW7, but found no mutations. Copy number loss of FBXW7, however was associated with enhanced genomic instability in the Complex breast tumor subtype, but instability may not be due to FBXW7 haploinsufficiency, since transcript levels were not reduced in tumors with loss of the locus, whereas reduced expression was observed for other neighboring genes involved in maintenance of genome stability. We also investigated whether cells deficient for FBXW7 showed enhanced instability by challenging cells with methotrexate and assessing numbers of genomic alterations arising in resistant cells. Although methotrexate resistant colonies formed at high frequencies in HCT116 FBXW7+/- and HCT116 FBXW7-/- cells compared to parental HCT116, few copy number alterations were detected in the resistant cells. Taken together these studies suggest that FBXW7 deficiency is unlikely to contribute to the extensive copy number aberrations associated with breast and possibly other tumor types.

}, keywords = {Breast Neoplasms, Cell Cycle Proteins, Cell Line, Tumor, Chromosomal Instability, Disease Progression, DNA, Drug Resistance, Neoplasm, Exons, F-Box Proteins, Genetic Techniques, Genomic Instability, Humans, Methotrexate, Mutation, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Ubiquitin-Protein Ligases}, issn = {0167-6806}, doi = {10.1007/s10549-007-9623-7}, author = {Byrd, Kristin N and Huey, Bing and Roydasgupta, Ritu and Fridlyand, Jane and A Snijders and Albertson, Donna G} } @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 {160, title = {Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer.}, journal = {Clin Cancer Res}, volume = {13}, year = {2007}, month = {2007 Oct 1}, pages = {5745-55}, abstract = {

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

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

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

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

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

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

}, keywords = {Breast Neoplasms, Computational Biology, Cytogenetic Analysis, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Humans, Oligonucleotide Array Sequence Analysis, Prognosis}, issn = {0829-8211}, doi = {10.1139/O07-072}, author = {Climent, J and Garcia, J L and Jiang-Hua Mao and Arsuaga, J and Perez-Losada, J} } @article {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 {269, title = {Breast tumor copy number aberration phenotypes and genomic instability.}, journal = {BMC Cancer}, volume = {6}, year = {2006}, month = {2006}, pages = {96}, abstract = {

BACKGROUND: Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal instability in tumors remain obscure. Genes likely to have genomic instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes.

METHODS: We applied array comparative genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of genomic instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of genomic instability.

RESULTS: We discriminated three breast tumor subtypes based on genomic DNA copy number alterations. The subtypes varied with respect to level of genomic instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies instability.

CONCLUSION: Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome.

}, keywords = {Adult, Aged, Breast Neoplasms, Carcinoma, Ductal, Breast, Chromosome Aberrations, Chromosomes, Human, DNA, Neoplasm, E2F Transcription Factors, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genes, p53, Genes, Retinoblastoma, Genomic Instability, Humans, Karyotyping, Middle Aged, Neoplasm Proteins, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Phenotype, Retinoblastoma Protein, Signal Transduction, Telomere}, issn = {1471-2407}, doi = {10.1186/1471-2407-6-96}, author = {Fridlyand, Jane and A Snijders and Ylstra, Bauke and Li, Hua and Olshen, Adam and Segraves, Richard and Dairkee, Shanaz and Tokuyasu, Taku and Ljung, Britt Marie and Jain, Ajay N and McLennan, Jane and Ziegler, John and Chin, Koei and Devries, Sandy and Feiler, Heidi and Gray, Joe W and Waldman, Frederic and Pinkel, Daniel and Albertson, Donna G} } @article {254, title = {Fully automatic quantification of microarray image data.}, journal = {Genome Res}, volume = {12}, year = {2002}, month = {2002 Feb}, pages = {325-32}, abstract = {

DNA microarrays are now widely used to measure expression levels and DNA copy number in biological samples. Ratios of relative abundance of nucleic acids are derived from images of regular arrays of spots containing target genetic material to which fluorescently labeled samples are hybridized. Whereas there are a number of methods in use for the quantification of images, many of the software systems in wide use either encourage or require extensive human interaction at the level of individual spots on arrays. We present a fully automatic system for microarray image quantification. The system automatically locates both subarray grids and individual spots, requiring no user identification of any image coordinates. Ratios are computed based on explicit segmentation of each spot. On a typical image of 6000 spots, the entire process takes less than 20 sec. We present a quantitative assessment of performance on multiple replicates of genome-wide array-based comparative genomic hybridization experiments. By explicitly identifying the pixels in each spot, the system yields more accurate estimates of ratios than systems assuming spot circularity. The software, called, runs on Windows platforms and is available free of charge for academic use.

}, keywords = {Breast Neoplasms, Female, Gene Expression Profiling, Humans, Image Processing, Computer-Assisted, Male, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Staining and Labeling, Tumor Cells, Cultured}, issn = {1088-9051}, doi = {10.1101/gr.210902}, author = {Jain, Ajay N and Tokuyasu, Taku A and A Snijders and Segraves, Richard and Albertson, Donna G and Pinkel, Daniel} }