Mutations of breast cancer susceptibility gene BRCA1 (17q21) confer an increased risk for breast, ovarian, and, possibly, prostate cancer. Prior studies have established putative roles for BRCA1 in cell cycle regulation, apoptosis, and DNA-damage response pathways. However, the reason that BRCA1 mutations result in these specific tumor types rather than a broad spectrum of cancers remains unclear. Our preliminary studies indicate that: l) BRCA1 selectively inhibits estrogen receptor (ER) signalling in human prostate, breast, and cervical cancer cells; and 2) in prostate cancer cell line DU-145, down-regulation of the p300, a transcriptional adaptor that functions as a co-activator for BR, contributes to BRCA1-mediated inhibition of ER signalling. We hypothesize that BRCA1 inhibits BR activity in mammary epithelium and that inhibition is due, in part, to modulation of expression of key co-factors, such as p300. This inhibition of ER activity could serve as a feedback mechanism to limit the extent Of estrogenic stimulation of mammal epithelial cell proliferation and, thereby, to suppress carcinogenesis. To test this hypothesis, we propose to carry out three specific aims. In SA1, we will extend our preliminary studies to examine the ability of BRCA1 to modulate ER signalling in various human breast and ovarian cancer cell lines; dissect which phase(s) of the ER-alpha activation pathway is targeted by BRCA1; and investigate the specificity of the findings by determining if BRCA1 represses other transcriptional pathways, including non-classical pathways of ER signalling. In SA2, we will examine the role of p3O0 in BRCA1-mediated inhibition of ER signalling by genetically manipulating p3O0 expression and activity; and we will assess the potential roles of other nuclear receptor coactivators and co-repressors as intermediaries through which BRCA1 regulates estrogenic signalling. In SA3, we will utilize a series of BRCA1 expression plasmids encoding truncation mutants, site-specific mutants, or both, to identify the region(s) of BRCA1 involved in modulation of ER signalling pathways. These studies will establish a mechanism to explain why BRCA1 mutations pre-dispose to breast cancer development. They will also identify down-stream intermediaries of BRCA1 that are potential therapeutic targets for breast cancer prevention and control.
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