.The long-term objective is to improve breast cancer prevention strategies. This project exploits genetically engineered mouse models representing clinically relevant molecular aberrations in estrogen signaling in parallel with human breast tissue from high-risk women to address three needs. One, on-going discovery of candidate in vivo biomarkers and pathways of intrinsic resistance. Two, development of a human tissue based system to parallel our mouse-based experimental models. Three, comparison of efficacy and mechanism of alternative agents to tamoxifen. Genetically engineered mice model the pathophysiology of some types of breast cancer found in high-risk women. Primary tissue from high-risk women represents the 'real thing'but as the tissue and cells are moved into in vitro environments to perform experiments they also become model systems. Fixed tissue and studies of gene expression at specific time points provide static but informative representations of the high-risk breast environment. New in vitro systems are needed to improve projections of predicted benefit to therapeutic agents in different genetic environments, to 'personalize'medical intervention. Objective1. Compare impact of alternative preventive agents raloxifene, letrozole and efatutazone to tamoxifen in genetic settings exhibiting or likely to exhibit intrinsi tamoxifen resistance. Objective 2. Create a living biobank of human primary non-malignant but 'high breast cancer risk'mammary epithelial cells. Investigate in vitro approaches for testing tamoxifen (and other candidate preventive agents in the future) sensitivity using this living biobank. Objective 3. Explore alternative schedules of administration to increase effectiveness and/or reduce toxicity for an alternative preventive agent efatutazone, a PPAR? agonist, which has potential to prevent both ER+ and ER- breast cancer. Methods: Employ five genetically engineered mouse models (combinations of conditional increased Esr1 (Estrogen Receptor alpha) or CYP19A1 (Aromatase) expression in mammary epithelial cells and mammary epithelial cell-targeted loss of full-length Brca1 with germline Trp53 haploinsufficiency) as well as primary human mammary epithelial cells in experiments that employ large-scale screening technologies (RNAseq and reverse phase protein microarrays), primary cell culture under different conditions (conditional reprogrammed cells, spheroid and mammosphere culture), with administration of different candidate preventive agents tamoxifen, raloxifene, letrozole and efatutazone. Relevance: Tamoxifen is the only Selective Estrogen Receptor Modulator (SERM) currently FDA- approved for breast cancer prevention in pre- and post-menopausal women with raloxifene approved for post- menopausal women. This study will provide a molecular understanding of how different genetic lesions influence preventive agent response, explore development of in vitro systems that could test preventive agent response in clinical samples, and test if different treatment schedules can improve the therapeutic ratio of the PPAR? agonist efatutazone.

Public Health Relevance

Intrinsic resistance to tamoxifen compromises its effectiveness as a breast cancer chemopreventative for some women. This project will identify genetic biomarkers of intrinsic tamoxifen resistance, develop an in vitro system to test tamoxifen sensitivity in clinical specimens, and investigate alternative preventive agents raloxifene, letrozole and efatutazone.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA112176-06A1
Application #
8627803
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Jhappan, Chamelli
Project Start
2004-12-23
Project End
2018-11-30
Budget Start
2013-12-02
Budget End
2014-11-30
Support Year
6
Fiscal Year
2014
Total Cost
$272,030
Indirect Cost
$97,091
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
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Mahmoodzadeh, Shokoufeh; Leber, Joachim; Zhang, Xiang et al. (2014) Cardiomyocyte-specific Estrogen Receptor Alpha Increases Angiogenesis, Lymphangiogenesis and Reduces Fibrosis in the Female Mouse Heart Post-Myocardial Infarction. J Cell Sci Ther 5:153
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Cabrera, M Carla; Díaz-Cruz, Edgar S; Kallakury, Bhaskar V S et al. (2012) The CDK4/6 inhibitor PD0332991 reverses epithelial dysplasia associated with abnormal activation of the cyclin-CDK-Rb pathway. Cancer Prev Res (Phila) 5:810-21
Nakles, Rebecca E; Shiffert, Maddalena Tilli; Diaz-Cruz, Edgar S et al. (2011) Altered AIB1 or AIB1ýý3 expression impacts ER* effects on mammary gland stromal and epithelial content. Mol Endocrinol 25:549-63

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