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BRCA1 Regulation of Progesterone Receptor Function in Breast Cancer
Background. The progesterone receptor (PR), plays a key role in mammary development, especially during pregnancy. Its role in breast cancer is not as well-defined as the estrogen receptor (ER-a); but epidemiologic, clinical, and experimental studies suggest that PR signaling can stimulate normal mammary epithelial proliferation and breast cancer development. Previously, we showed that the BRCA1 protein interacts with ER-a and inhibits its activity. Preliminary studies suggest that BRCA1 interacts physically with PR and inhibits its transcriptional activity and that progesterone stimulates growth of the adult mammary gland in Brca1-deficient mice.
Hypothesis. We hypothesize that BRCA1 interacts physically and functionally with PR and inhibits its proliferation stimulatory action in the mammary gland, thus contributing to mammary tumor suppression.
Specific Aims. To test this hypothesis, we will carry out three aims: SA1. To map the interacting sites in the BRCA1 and PR proteins; SA2. To identify the mechanism(s) by which BRCA1 inhibits PR activity; and SA3. To determine if progesterone stimulates mammary tumorigenesis in mice with a conditional mammary-targeted Brca1 deletion.
Study Design. In SA1, we will map the BRCA1:PR physical interaction using GST capture, IP-Western blotting, confocal microscopy, and molecular modeling. In SA2, we will determine which stage(s) of PR activation are inhibited by BRCA1 using assays of ligand binding, DNA & chromatin binding, and coactivator binding. In SA3, we will test the ability of exogenous progesterone to stimulate mammary growth and tumorigenesis in mice with a mammary-targeted conditional deletion of Brca1 exon 11.
Potential Outcomes & Benefits. This study will address a key issue in breast cancer etiology: why early first pregnancy stimulates breast cancer development in BRCA1 mutation carriers, while it is protective in the general population. Pregnancy is associated high circulating progesterone levels, which contribute to mammary growth and differentiation. Our findings suggest that inactivation of BRCA1 will enhance progesterone-stimulated mammary growth, thus overriding the protective effect of pregnancy. This study may provide a rationale to use combined anti-estrogen and anti-progestin to prevent breast cancer in BRCA1 carriers. Up to 50% of sporadic breast cancers exhibit reduced or absent BRCA1 expression and/or haplo-insufficiency for BRCA1. This study may provide a rationale for anti-progestin therapy in the subset of breast cancers that are PR positive and exhibit reduced expression of BRCA1.
Background. Inherited defects (mutations) of the BRCA1 gene account for 2-3% of all breast cancers. However, the BRCA1 gene is often inactivated (under-expressed) in sporadic (ie., non-hereditary) breast cancers. Thus, the under-expression of BRCA1 may contribute to many cancers. Preliminary studies suggest that the BRCA1 protein physically binds to and inhibits the activity of the progesterone receptor (PR), a protein that mediates the action of progesterone, a hormone that regulates normal breast epithelial cell growth, particularly during pregnancy. Progesterone caused excessive mammary growth in BRCA1-deficient mice, suggesting that BRCA1 restrains the growth stimulation due to progesterone.
Hypothesis. We hypothesize that BRCA1 binds to PR, inhibits its activity, and thereby blocks the mammary growth and tumor-promoting action of progesterone.
Specific Aims. To substantiate this hypothesis, we propose to: 1. map the sites within the BRCA1 and PR proteins that physically interact; 2. identify the mechanism(s) by which BRCA1 inhibits PR activity; and 3. determine if progesterone causes increased mammary tumor formation in mice with defective Brca1 genes in their mammary glands.
Study Design. We will employ state-of-the-art molecular/cellular biologic approaches to: 1) identify the exact site(s) on BRCA1 where PR binds and vice versa; and 2) determine which stage(s) of the PR activation process (eg., progesterone binding to PR; PR binding to DNA; interaction of PR with coactivators) are blocked by BRCA1. In aim 3, we will test the ability of added progesterone to cause mammary growth and tumor formation in mice genetically engineered to delete both Brca1 genes from the mammary glands.
Potential Outcomes & Benefits. These studies may impact breast cancer biology and control. Unlike sporadic cancers for which pregnancy confers a risk-reduction, pregnancy increases the risk of breast cancer in women with BRCA1 mutations, an unexplained finding. If our hypothesis is correct, it would explain why pregnancy increases breast cancer risk in these women, since circulating progesterone levels are very high during pregnancy. Existing data suggest that Tamoxifen, an anti-estrogen, may not prevent breast cancer in women with BRCA1 mutations. If we are correct, it is possible that women with BRCA1 mutations may require an anti-progestin in addition to an anti-estrogen to prevent breast cancer. Our findings may suggest the use of anti-progestins in a subgroup of women with sporadic breast cancers that are PR positive but express insufficient BRCA1 to inhibit PR.