The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-a] 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-a activity and that domains within the amino-and carboxyltermini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-a 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-a in vivo and to bind to ER-a 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-a. Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-a binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-a activity. Our ®ndings suggest that the aminoterminus of BRCA1 interacts with ER-a, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain. Oncogene (2001) 20, 77 ± 87.
These findings suggest that significant titers of IL-1beta are present within the microenvironment of most breast carcinomas and that a high IL-1beta content is often associated with tumor invasiveness and with other pathologic features suggestive of an aggressive tumor biology.
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