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- Title
Role of direct interaction in BRCA1 inhibition of estrogen receptor activity.
- Authors
Fan, Saijun; Ma, Yong Xian; Wang, Chenguang; Yuan, Ren-qi; Meng, Qinghui; Wang, Ji-An; Erdos, Michael; Goldberg, Itzhak D; Webb, Paul; Kushner, Peter J; Pestell, Richard G; Rosen, Eliot M
- Abstract
The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-α] in human breast and prostate cancer cell lines. In this study, we found that breast cancer-associated mutations of BRCA1 abolish or reduce its ability to inhibit ER-α activity and that domains within the amino- and carboxyl-termini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-α activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 (HCC1937). In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. The BRCA1 protein was found to associate with ER-α in vivo and to bind to ER-α in vitro, by an estrogen-independent interaction that mapped to the amino-terminal region of BRCA1 (ca. amino acid 1-300) and the conserved carboxyl-terminal activation function [AF-2] domain of ER-α. Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-α binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-α activity. Our findings suggest that the amino-terminus of BRCA1 interacts with ER-α, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain. Oncogene (2001) 20, 77–87.
- Subjects
ESTROGEN receptors; BREAST cancer
- Publication
Oncogene, 2001, Vol 20, Issue 1, p77
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1204073