title: Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells.
abstract: Mutational inactivation of BRCA1 confers increased risk for breast cancer. However, the underlying basis for the breast tissue-restricted, tumor-suppressive properties of BRCA1 remains poorly defined. Here, we show that BRCA1 and the estrogen receptor alpha (ER-alpha) modulated vascular endothelial growth factor (VEGF) gene transcription and secretion in breast cancer cells. ER-alpha interacted in vitro and in vivo with BRCA1, and this interaction was mediated by the AF-2 domain of ER-alpha and two domains of BRCA1, the amino-acid residues 1-306 and 428-683. Endogenous interaction of ER-alpha with BRCA1 was observed in normal MCF-10A breast epithelial cells and in breast cancer cells (MCF-7 and T47D), and this interaction was significantly reduced in the presence of estrogen. Furthermore, ER-alpha induced activation of VEGF gene transcription, using human VEGF promoter-luciferase reporter constructs. The AF-2 domain of ER-alpha was also shown to induce VEGF gene transcription activation similar to that obtained with the full-length ER-alpha. However, in the presence of BRCA1, VEGF gene transcription activation and VEGF protein secretion were significantly inhibited in a dose-dependent manner. The BRCA1 domain of 1-683 amino acid residues was required for this inhibition of VEGF gene transcription activation. Three mutated forms of BRCA1 (A1708E, M1775R and Y1853X), that have been identified in familial breast cancers, failed to associate with ER-alpha and to suppress VEGF promoter activity and VEGF protein secretion. Overexpression of wild-type BRCA1 in HCC-1937 breast cancer cells that lack endogenous functional BRCA1 significantly reduced VEGF secretion in these cells. These results demonstrate a novel pathogenic mechanism whereby mutations in BRCA1, via their interaction with ER-alpha, could promote tumorigenesis through the hormonal regulation of mammary epithelial cell proliferation and impaired VEGF function, which may lead to cancer growth and angiogenesis.
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 4 Blackfan Circle, Boston, Massachusetts, MA 02115, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kawai
authors.forename: Huchun
authors.initials: H
authors.lastname: Li
authors.forename: Philip
authors.initials: P
authors.lastname: Chun
authors.forename: Shalom
authors.initials: S
authors.lastname: Avraham
authors.forename: Hava Karsenty
authors.initials: HK
authors.lastname: Avraham
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D019313:BRCA1 Protein; D016228:Endothelial Growth Factors; D047628:Estrogen Receptor alpha; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors