17-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 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 electrophoretic mobility shift assays support a role for Sp proteins in hormone-dependent downregulation of VEGFR2 in MCF-7 cells, primarily through ER/Sp1 and ER/Sp3 interactions with the VEGFR2 promoter. Using chromatin immunoprecipitation and transient transfection/RNA interference assays we show that the ER/Sp protein-promoter interactions are accompanied by recruitment of the corepressors SMRT and NCoR to the promoter and that SMRT and NCoR knockdown reverse E2-mediated downregulation 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.