BRCA1 Regulation of Estrogen Signaling in the Breast
Addendum to final rept. 1 May 2006-30 Apr 2007
TEXAS UNIV AT SAN ANTONIO HEALTH SCIENCE CENTER
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Mutational inactivation of BRCA1 confers a cumulative lifetime risk of breast and ovarian cancers. However, the underlying basis for the tissue-specific tumor suppressor function of BRCA1 remains poorly defined. Previously, we described a novel function for BRCA1 in suppressing the ligand-independent transcriptional activity of the estrogen receptor alpha ER alpha, a principal determinant of the growth and differentiation of breasts and ovaries. Based on these observations, we hypothesized that BRCA1 represents a ligand-reversible barrier to transcriptional activation by unliganded ER alph and, further, that mutational inactivation of BRCA1 promotes epithelial cell proliferation through aberrant expression of estrogen-responsive genes, possibly contributing to tumorigenesis. To substantiate this hypothesis we have proposed the following aims 1 to biochemically reconstitute BRCA1-mediated ligand-independent repression of ER alpha in vitro 2 to examine the role of estrogen-induced site-specific BRCA1 phosphorylation in the regulation of BRCA1-mediated ligand-independent ER alpha repression and 3 to determine the role of BRCA1 in the control of paracrine growth signaling in the breast. Collectively, these studies should reveal novel insight into the tissue-specific tumor suppressor function of BRCA1 and provide defined molecular targets for future intervention in breast cancer.
- Medicine and Medical Research