BRCA1 Mediates Ligand-Independent Transcriptional Repression of the Estrogen Receptor

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 17; pp. 9587 - 9592
• Main Authors: Zheng, Lei, Annab, Lois A., Afshari, Cynthia A., Lee, Wen-Hwa, Boyer, Thomas G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.08.2001; National Acad Sciences
• Subjects: Adenocarcinoma - pathology; Animals; Biochemistry; Biological Sciences; BRAC1 protein; BRCA1 Protein - physiology; Breast cancer; Breast Neoplasms - pathology; Cathepsin D - biosynthesis; Cathepsin D - genetics; Cell growth; Cell lines; Cells, Cultured; Cellular immunity; DNA-Binding Proteins; Epithelial cells; Estradiol - pharmacology; Estrogen Receptor alpha; Estrogens; Female; Fibroblasts - metabolism; Fungal Proteins - genetics; Gene Silencing; Genes; Genes, BRCA1; Genes, p53; Histone Deacetylases - metabolism; Humans; Ligands; Mice; Mice, Knockout; Mutation, Missense; Neoplasms, Hormone-Dependent - pathology; Ovarian cancer; Ovarian Neoplasms - pathology; Plasmids; Protein Biosynthesis; Proteins; Proteins - genetics; Receptors; Receptors, Estrogen - biosynthesis; Receptors, Estrogen - genetics; Receptors, Progesterone - biosynthesis; Receptors, Progesterone - genetics; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Repression; Reverse Transcriptase Polymerase Chain Reaction; Saccharomyces cerevisiae Proteins; Transactivation; Transcription Factors - genetics; Transcriptional Activation; Transfection; Trefoil Factor-1; Tumor Suppressor Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.171174298

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.