Vascular endothelial growth factor receptor-2 expression is induced by 17β-estradiol in ZR-75 breast cancer cells by estrogen receptor α/Sp proteins

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

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Vascular endothelial growth factor receptor-2 kinase insert domain receptor (VEGFR2/KDR) is critical for angiogenesis, and VEGFR2 mRNA and protein are expressed in ZR-75 breast cancer cells and induced by 17β-estradiol (E2). Deletion analysis of the VEGFR2 promoter indicates that the proximal GC-rich region is required for both basal and hormone-induced transactivation, and mutation of one or both of the GC-rich motifs at -58 and -44 results in loss of transactivation. Electrophoretic mobility shift and chromatin immunoprecipitation assays show that Sp1, Sp3, and Sp4 proteins bind the GC-rich region of the VEGFR2 promoter. Results of the chromatin immunoprecipitation assay also demonstrate that ERα is constitutively bound to the VEGFR2 promoter and that these interactions are not enhanced after treatment with E2, whereas ERα binding to the region of the pS2 promoter containing an estrogen-responsive element is enhanced by E2. RNA interference studies show that hormone-induced activation of the VEGFR2 promoter constructs requires Sp3 and Sp4 but not Sp1, demonstrating that hormonal activation of VEGFR2 involves a nonclassical mechanism in which ERα/ Sp3 and ERα/Sp4 complexes activate GC-rich sites where Sp proteins but not ERα bind DNA. These results show for the first time that Sp3 and Sp4 cooperatively interact with ERα to activate VEGFR2 and are in contrast to previous results showing that several hormone-responsive genes are activated by ERα/Sp1 in breast cancer cell lines.

Original languageEnglish (US)
Pages (from-to)3285-3295
Number of pages11
JournalEndocrinology
Volume147
Issue number7
DOIs
StatePublished - 2006

ASJC Scopus subject areas

  • Endocrinology

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