BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor

Lei Zheng, Lois A. Annab, Cynthia A. Afshari, Wen Hwa Lee, Thomas G. Boyer

Research output: Contribution to journalArticle

180 Scopus citations

Abstract

Mutational inactivation of BRCA1 confers a cumulative lifetime risk of breast and ovarian cancers. However, the underlying basis for the tissue-restricted tumor-suppressive properties of BRCA1 remains poorly defined. Here we show that BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor α (ERα), a principal determinant of the growth, differentiation, and normal functional status of breasts and ovaries. In Brca1-null mouse embryo fibroblasts and BRCA1-deficient human ovarian cancer cells, ERα exhibited ligand-independent transcriptional activity that was not observed in Brca1-proficient cells. Ectopic expression in Brca1-deficient cells of wild-type BRCA1, but not clinically validated BRCA1 missense mutants, restored ligand-independent repression of ERα in a manner dependent upon apparent histone deacetylase activity. In estrogen-dependent human breast cancer cells, chromatin immunoprecipitation analysis revealed the association of BRCA1 with ERα at endogenous estrogen-response elements before, but not after estrogen stimulation. Collectively, these results reveal BRCA1 to be a ligand-reversible barrier to transcriptional activation by unliganded promoter-bound ERα and suggest a possible mechanism by which functional inactivation of BRCA1 could promote tumorigenesis through inappropriate hormonal regulation of mammary and ovarian epithelial cell proliferation.

Original languageEnglish (US)
Pages (from-to)9587-9592
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number17
DOIs
StatePublished - Aug 14 2001

ASJC Scopus subject areas

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