title: BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor.
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.
authors.affiliation: Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio 78245, USA. leew@uthscsa.edu
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.forename: L A
authors.initials: LA
authors.lastname: Annab
authors.forename: C A
authors.initials: CA
authors.lastname: Afshari
authors.forename: W H
authors.initials: WH
authors.lastname: Lee
authors.forename: T G
authors.initials: TG
authors.lastname: Boyer
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D019313:BRCA1 Protein / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology; D002402:Cathepsin D / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D004967:Estrogens; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics; D020868:Gene Silencing; D019398:Genes, BRCA1; D016158:Genes, p53; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology; D010051:Ovarian Neoplasms / Q000473:pathology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics*; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins
chemical_list: D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D008024:Ligands; D011506:Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; C051838:TFF1 protein, human; D014157:Transcription Factors; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D004958:Estradiol; D002402:Cathepsin D; D006655:Histone Deacetylases