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Endocrinology Vol. 144, No. 6 2325-2335
Copyright © 2003 by The Endocrine Society

Estrogen Receptor/Sp1 Complexes Are Required for Induction of cad Gene Expression by 17ß-Estradiol in Breast Cancer Cells

Shaheen Khan, Maen Abdelrahim, Ismael Samudio and Stephen Safe

Department of Veterinary Physiology and Pharmacology Texas A&M University, College Station, Texas 77843-4466

Address all correspondence and requests for reprints to: Stephen Safe, Department of Veterinary Physiology and Pharmacology Texas A&M University 4466 TAMU, Veterinary Research Building 409, College Station, Texas 77843-4466. E-mail: ssafe{at}cvm.tamu.edu.

The cad gene is trifunctional and expresses carbamoylphosphate synthetase/aspartate carbamyltransferase/dihydroorotase, which are required for pyrimidine biosynthesis. Cad gene activities are induced in MCF-7 human breast cancer cells, and treatment of MCF-7 or ZR-75 cells with 10 nM 17ß-estradiol (E2) resulted in a 3- to 5-fold increase in cad mRNA levels in both cell lines. The mechanism of hormone-induced cad gene expression was further investigated using constructs containing the growth-responsive -90 to +115 (pCAD1) region of the cad gene promoter. E2 induced reporter gene (luciferase) activity in MCF-7 and ZR-75 cells transfected with pCAD1, which contains three upstream GC-rich and two downstream E-box motifs. Deletion and mutation analysis of the cad gene promoter demonstrated that only the GC boxes that bind Sp1 protein were required for E2 responsiveness. Results of electrophoretic mobility shift and chromatin immunoprecipitation assays show that both Sp1 and estrogen receptor {alpha} interact with the GC-rich region of the cad gene promoter. Moreover, in transactivation assays with pCAD1, hormone-induced transactivation was inhibited by cotransfection with dominant-negative Sp1 expression plasmid and small inhibitory RNA for Sp1, which silences Sp1 expression in the cells. These results demonstrate that, in common with many other genes involved in E2-induced cell proliferation, the cad gene is also regulated by a nonclassical ER{alpha}/Sp1-mediated pathway.




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