BRCA1 Regulation of Estrogen Signaling in the Breast
Abstract
Mutational inactivation of BRCAl confers a cumulative lifetime risk of breast and ovarian cancers. However, the underlying basis for the tissue-specific tumor suppressor properties of BRCAl remains poorly defined. Previously, we described a novel function for BRCAl 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 BRCAl represents a ligand-reversible barrier to transcriptional activation by unliganded ER alpha and, further, that mutational inactivation of BRCAl promotes breast 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 BRCAl-mediated ligand-independent repression of ER alpha in vitro; (2) to examine the role of estrogen-induced site-specific BRCAl phosphorylation in the regulation of BRCAl-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 BRCAl and provide defined molecular targets for future intervention in breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2004
- Accession Number
- ADA425657
Entities
People
- Thomas G. Boyer
Organizations
- University of Texas Health Science Center at San Antonio