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Hormonal Prevention of Tumorigenesis in the BRCA1 Mutant Mammary Gland
Background: Early full term pregnancy in women is associated with a significantly reduced risk of breast cancer development. Early hormone-induced protection has also been mimicked in rodents where 3 week treatment of young mice with estrogen (E) and progesterone (P) protected from tumors stimulated by chemical carcinogen. The E+P-dependent refractory phenotype is associated with persistent changes in the expression of several growth factor mediators of mammary epithelial cell proliferation in the involuted mammary gland. Women with a BRCA1 mutation have a highly significant increase in life time risk of developing breast cancer compared to the general population. Mice with BRCA1 selectively inactivated in the mammary gland (BRCA1co/co) form spontaneous mammary tumors after 10 months of age and with haploid loss of p53, tumor formation is further accelerated. BRCA1co/co adult mice treated with P have increased mammary gland volume and tertiary side-branching. This P-specific response implies that its receptor, PR, may to contribute to tumor susceptibility in BRCA1co/co mice. Hypothesis: Early exposure to pregnancy levels of E+P may lead to a phenotype in the BRCA1 mutant mammary gland that is refractory to tumorigenesis. Specific Aims: 1) To identify whether early treatment with E+P induces a refractory phenotype to tumorigenesis in BRCA1co/co/p53+/- mice. 2) To examine the cellular and molecular changes in the mammary gland that accompany E+P dependent induction of a refractory phenotype to tumorigenesis in BRCA1co/co/p53+/- mice. 3) To analyze the contribution of PR to the development of spontaneous tumors in BRCA1co/co/p53+/- mice by analysis of the consequences of PR ablation (PRKO) on tumor development. Study Design: At 5 weeks of age, BRCA1co/co/p53+/- mice will be treated with E+P or control for 3 weeks and then monitored for mammary tumor formation. Histology of all tissues will be examined and tumor latency analyzed. For analysis of cellular and molecular changes, mice will be treated as above and mammary gland tissue will be collected at 2 and 21 days after E+P treatment and after involution. Differential expression of markers of the involuted refractory gland in E+P treated versus untreated glands will be examined by real-time qPCR and confirmed by immunohistochemistry. To investigate whether PR plays a role in tumorigenesis in BRCA1 mutant mammary gland we will cross BRCA1co/co /p53+/- with PRKO mice and monitor for tumor formation. Potential Outcomes and Benefits of the Research: This research will provide valuable information that will have an impact on prevention strategies for women at high risk of developing breast cancer due to a BRCA1 mutation. Furthermore, if PR is found to be implicated in BRCA1-dependent tumorigenesis this study will provide a preclinical rational to re-explore the role of antiprogestins in the protection from breast cancer in BRCA1 mutation carriers.
Rational for this proposal: Almost half of hereditary breast cancers and 90% of familial breast and ovarian cancer are due to mutations in the breast cancer susceptibility gene, BRCA1. Approximately 80% of women with a mutation in the BRCA1 gene are at risk of developing breast cancer by the age of 70 years. In the general population, pregnancy at an early age is highly protective against breast cancer development where women who are