Mammary Gland Cancer

Barkan, Dalit; Montagna, Cristina; Ried, Thomas; Green, Jeffrey E.

doi:10.1002/0471675067.mmc007

Cited by 6 publications

(4 citation statements)

References 212 publications

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“…These studies will determine how the primary genetic mutation influences accumulation of secondary mutations to affect tumor development. This work will complement earlier work using CGH based on hybridizations to chromosomal spreads (Barkan et al 2004). Our preliminary data suggest that there are particular genomic changes associated with the initiating genetic mutation within some of the models (M. Zhu, unpublished data).…”

Section: Genomic Changes Related To the Subtype Of Breast Cancersupporting

confidence: 65%

Genomic Analyses as a Guide to Target Identification and Preclinical Testing of Mouse Models of Breast Cancer

Bennett

Green

2010

Toxicol Pathol

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Cross-species genomic analyses have proven useful for identifying common genomic alterations that occur in human cancers and mouse models designed to recapitulate human tumor development. High-throughput molecular analyses provide a valuable tool for identifying particular animal models that may represent aspects of specific subtypes of human cancers. Corresponding alterations in gene copy number and expression in tumors from mouse and human suggest that these conserved changes may be mechanistically essential for cancer development and progression, and therefore, they may be critical targets for therapeutic intervention. Using a cross-species analysis approach, mouse models in which the functions of p53, Rb, and BRCA1 have been disrupted demonstrate molecular features of human, triple-negative (ER-, PR-, and ERBB2-), basal-type breast cancer. Using mouse tumor models based on the targeted abrogation of p53 and Rb function, we identified a large, integrated genetic network that correlates to poor outcome in several human epithelial cancers. This gene signature is highly enriched for genes involved in DNA replication and repair, chromosome maintenance, cell cycle regulation, and apoptosis. Current studies are determining whether inactivation of specific members within this signature, using drugs or siRNA, will identify potentially important new targets to inhibit triple-negative, basal-type breast cancer for which no targeted therapies currently exist.

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Section: Genomic Changes Related To the Subtype Of Breast Cancersupporting

confidence: 65%

Genomic Analyses as a Guide to Target Identification and Preclinical Testing of Mouse Models of Breast Cancer

Bennett

Green

2010

Toxicol Pathol

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“…This difference may be associated with the fact that high expression of oncogenes, as seen using the MMTV promoter, may require fewer genomic alterations for tumorigenesis than present in models based upon endogenous promoter-driven gene expression or loss of suppressor gene functions, especially those involved in genome stability such as p53 and BRCA1. Overall, it appears that DNA copy number changes are less prevalent in the oncogene-driven GEM models compared with models in which genetic alterations lead to genomic instability [ 36 ]. This distinction in rate of tumor progression and accumulation of genetic mutations between GEM models and human breast tumors is important and should be considered when choosing GEM models to represent subtypes of human breast cancer.…”

Section: Dna Copy Number Changesmentioning

confidence: 99%

Unlocking the power of cross-species genomic analyses: identification of evolutionarily conserved breast cancer networks and validation of preclinical models

Bennett

Green

2008

Breast Cancer Res

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The application of high-throughput genomic technologies has revealed that individual breast tumors display a variety of molecular features that require more personalized approaches to treatment. Several recent studies have demonstrated that a cross-species analytic approach provides a powerful means to filter through genetic complexity by identifying evolutionarily conserved genetic networks that are fundamental to the oncogenic process. Mousehuman tumor comparisons will provide insights into cellular origins of tumor subtypes, define interactive oncogenetic networks, identify potential novel therapeutic targets, and further validate as well as guide the selection of genetically engineered mouse models for preclinical testing. IntroductionWithin the past decade, high-throughput genomic technologies have revolutionized the study of breast cancer. Molecularly distinct tumor subtypes of human breast cancer have been identified and appear to arise from distinct progenitor lineages. These subtypes display gene expression signatures that are predictive for disease progression, prognosis, and response to therapy. Since survival rates for breast cancer have improved relatively little over the past two decades, this high-definition molecular characterization of tumor subtypes has the potential to offer new avenues for discovery of novel therapeutic targets to treat breast cancer. However, genetic complexity in diverse human populations, differences between experimental platforms, experimental designs, and improper statistical analyses [1] have contributed to the tremendous challenges of identifying the functionally most significant gene signatures and genetic networks that are critical to the oncogenic process.One approach to improving the discovery of important genetic networks involved in cancer development and progression has been to use relevant genetically engineered mouse (GEM) models of mammary cancer in mouse-human comparisons to identify evolutionarily conserved genetic alterations shared in tumorigenesis in the two species. Recent work from several groups has applied this analytic approach to a number of cancer types, including breast cancer. This review will focus on how cross-species comparisons of gene expression, genome copy number changes, and bioinformatic analyses have improved our understanding of how particular mammary cancer models represent specific subtypes of human breast cancer. These analyses have led to an increased understanding of the cellular origins of the subtypes of breast cancer, distinctions between molecular networks in different tumor subtypes, stem cell biology, genes involved in metastatic progression, and improved selection of GEM models for preclinical testing of preventive and therapeutic strategies. Identification of evolutionarily conserved genetic alterations in breast cancer subtypes through mouse-human gene expression comparisonsAt least five molecularly distinct subtypes of breast cancer have been identified through the use of high-throughput genomic technologies [2,...

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“…To address the complexity and heterogeneity of breast cancer in vivo, numerous genetically engineered mouse (GEM) models of mammary cancer have been developed to recapitulate some of the known genetic and biologic interactions occurring in human breast cancer (Van Dyke and Jacks 2002). These models provide tremendous insight into the molecular biology of breast cancer pathogenesis, including growth factors, oncogenes, tumor suppressor genes, and cell cycle regulators (Barkan et al 2004; Kavanaugh et al 2002). …”

Section: Introductionmentioning

confidence: 99%

Pathologic progression of mammary carcinomas in a C3(1)/SV40 T/t-antigen transgenic rat model of human triple-negative and Her2-positive breast cancer

et al. 2010

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The C3(1) component of the rat prostate steroid binding protein has been used to target expression of the SV40 T/t-antigen to the mammary epithelium of mice resulting in pre-neoplastic lesions that progress to invasive and metastatic cancer with molecular features of human basal-type breast cancer. However, there are major differences in the histologic architecture of the stromal and epithelial elements between the mouse and human mammary glands. The rat mammary gland is more enriched with epithelial and stromal components than the mouse and more closely resembles the cellular composition of the human gland. Additionally, existing rat models of mammary cancer are typically estrogen receptor positive and hormone responsive, unlike most genetically engineered mouse mammary cancer models. In an attempt to develop a mammary cancer model that might more closely resemble the pathology of human breast cancer, we generated a novel C3(1)/SV40 T/t-antigen transgenic rat model that developed progressive mammary lesions leading to highly invasive adenocarcinomas. However, aggressive tumor development prevented the establishment of transgenic lines. Characterization of the tumors revealed that they were primarily estrogen receptor and progesterone receptor negative, and either her2/neu positive or negative, resembling human triple-negative or Her2 positive breast cancer. Tumors expressed the basal marker K14, as well as the luminal marker K18, and were negative for smooth muscle actin. The triple negative phenotype has not been previously reported in a rat mammary cancer model. Further development of a C3(1)SV40 T/t-antigen based model could establish valuable transgenic rat lines that develop basal-type mammary tumors.

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Mammary Gland Cancer

Cited by 6 publications

References 212 publications

Genomic Analyses as a Guide to Target Identification and Preclinical Testing of Mouse Models of Breast Cancer

Genomic Analyses as a Guide to Target Identification and Preclinical Testing of Mouse Models of Breast Cancer

Unlocking the power of cross-species genomic analyses: identification of evolutionarily conserved breast cancer networks and validation of preclinical models

Pathologic progression of mammary carcinomas in a C3(1)/SV40 T/t-antigen transgenic rat model of human triple-negative and Her2-positive breast cancer

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