Role of direct interaction in BRCA1 inhibition of estrogen receptor activity

Saijun Fan, Yong Xian Ma, Chenguang Wang, Ren Qi Yuan, Qinghui Meng, Ji An Wang, Michael Erdos, Itzhak D. Goldberg, Paul Webb, Peter J. Kushner, Richard G. Pestell, Eliot M. Rosen

Research output: Contribution to journalArticle

214 Scopus citations

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 art, 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.

Original languageEnglish (US)
Pages (from-to)77-87
Number of pages11
JournalOncogene
Volume20
Issue number1
DOIs
StatePublished - Jan 4 2001

Keywords

  • Activation function-2 (AF-2)
  • BRCA1
  • Breast cancer
  • Estrogen receptor (ER)

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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