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Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9587-92. Epub 2001 Aug 7.

BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor.

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1
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio 78245, USA. leew@uthscsa.edu

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 alpha (ERalpha), 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, ERalpha 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 ERalpha 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 ERalpha 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 ERalpha 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.

PMID:
11493692
PMCID:
PMC55496
DOI:
10.1073/pnas.171174298
[Indexed for MEDLINE]
Free PMC Article

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