Vascular endothelial growth factor receptor-2 expression is down-regulated by 17β-estradiol in MCF-7 breast cancer cells by estrogen receptor α/Sp proteins

Kelly J. Higgins, Shengxi Liu, Maen Abdelrahim, Kathryn Vanderlaag, Xinyi Liu, Weston Porter, Richard Metz, Stephen Safe

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

17β-Estradiol (E2) induces and represses gene expression in breast cancer cells; however, the mechanisms of gene repression are not well understood. In this study, we show that E2 decreases vascular endothelial growth factor receptor 2 (VEGFR2) mRNA levels in MCF-7 cells, and this gene was used as a model for investigating pathways associated with E2-dependent gene repression. Deletion analysis of the VEGFR2 promoter indicates that the proximal GC-rich motifs at -58 and -44 are critical for the E2-dependent decreased response in MCF-7 cells. Mutation or deletion of these GC-rich elements results in loss of hormone responsiveness and shows that the -60 to -37 region of the VEGFR2 promoter is critical for both basal and hormone-dependent decreased VEGFR2 expression in MCF-7 cells. Western blot, immunofluorescent staining, RNA interference, and EMSAs support a role for Sp proteins in hormone-dependent down-regulation of VEGFR2 in MCF-7 cells, primarily through estrogen receptor (ER)α/Sp1 and ERα/Sp3 interactions with the VEGFR2 promoter. Using chromatin immunoprecipitation and transient transfection/RNA interference assays we show that the ERα/Sp protein-promoter interactions are accompanied by recruitment of the corepressors SMRT (silencing mediator of retinoid and thyroid hormone receptor) and NCoR (nuclear receptor corepressor) to the promoter and that SMRT and NCoR knock-down reverse E2-mediated down-regulation of VEGFR2 expression in MCF-7 cells. This study illustrates that both SMRT and NCoR are involved in E2-dependent repression of VEGFR2 in MCF-7 cells.

Original languageEnglish (US)
Pages (from-to)388-402
Number of pages15
JournalMolecular Endocrinology
Volume22
Issue number2
DOIs
StatePublished - Feb 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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