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Submitted on January 20, 2006
Accepted on March 22, 2006
-Estradiol In ZR-75 Breast Cancer Cells By Estrogen Receptor 
/Sp Proteins
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843; Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030; Department of Veterinary Physiology and Pharmacology, Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX 77843
* To whom correspondence should be addressed. E-mail: ssafe{at}cvm.tamu.edu.
Vascular endothelial growth factor receptor-2 (VEGFR2/KDR) is critical for angiogenesis, and VEGFR2 mRNA and protein are expressed in ZR-75 breast cancer cells and induced by 17
-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 (ChIP) assays show that Sp1, Sp3, and Sp4 proteins bind the GC-rich region of the VEGFR2 promoter. Results of the ChIP assay also demonstrate that ER
is constitutively bound to the VEGFR2 promoter and that these interactions are not enhanced after treatment with E2; whereas ER 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 non-classical mechanism in which ER/Sp3 and ER/Sp4 complexes activate GC-rich sites where Sp proteins but not ER bind DNA. These results show for the first time that Sp3 and Sp4 cooperatively interact with ER to activate VEGFR2 and are in contrast to previous results showing that several hormone-responsive genes are activated by ER/Sp1 in breast cancer cell lines.
/Sp
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