Journal
ONCOGENE
Volume 20, Issue 1, Pages 77-87Publisher
SPRINGERNATURE
DOI: 10.1038/sj.onc.1204073
Keywords
BRCA1; estrogen receptor (ER); breast cancer; activation function-2 (AF-2)
Funding
- NCI NIH HHS [R01-CA70897] Funding Source: Medline
- NIEHS NIH HHS [R01-ES09169 , +] Funding Source: Medline
- PHS HHS [R01-82599] Funding Source: Medline
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The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] 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-alpha activity and that domains within the amino- and carboxyl-termini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-alpha 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-alpha in vivo and to bind to ER-alpha 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-alpha, Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-alpha binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-alpha activity. Our findings suggest that the amino-terminus of BRCA1 interacts with ER-alpha, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain.
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