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Vascular Endothelial Growth Factor Receptor-2 Expression Is Down-Regulated by 17β-Estradiol in MCF-7 Breast Cancer Cells by Estrogen Receptor /Sp Proteins

Department of Biochemistry and Biophysics (K.J.H., X.L., S.S.), Department of Veterinary Physiology and Pharmacology (K.V., S.S.), and Department of Veterinary Integrated Biosciences (W.P., R.M.), Texas A&M University, College Station, Texas 77843; and Institute of Biosciences and Technology (S.L., M.A., S.S.), Texas A&M Health Science Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, Texas 77843-4466. E-mail: ssafe{at}cvm.tamu.edu.

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)/Sp1 and ER/Sp3 interactions with the VEGFR2 promoter. Using chromatin immuno-precipitation and transient transfection/RNA in-terference assays we show that the ER/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 knockdown 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   NCOR  |  SMRT

Ligands:   17β-Estradiol  |  Fulvestrant

This article has been cited by other articles:

				F. Wu, I. Ivanov, R. Xu, and S. Safe Role of SP transcription factors in hormone-dependent modulation of genes in MCF-7 breast cancer cells: microarray and RNA interference studies J. Mol. Endocrinol., January 1, 2009; 42(1): 19 - 33. [Abstract] [Full Text] [PDF]

				S. Safe and K. Kim Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways J. Mol. Endocrinol., November 1, 2008; 41(5): 263 - 275. [Abstract] [Full Text] [PDF]