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*ESTRADIOL
Endocrinology Vol. 141, No. 7 2439-2449
Copyright © 2000 by The Endocrine Society

ARTICLES

Transcriptional Activation of Thymidylate Synthase by 17ß-Estradiol in MCF-7 Human Breast Cancer Cells1

Wen Xie, Reqin Duan, Ichen Chen, Ismael Samudio and Stephen Safe2

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

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

Thymidylate synthase (TS) catalyzes methylation of deoxyuridine phosphate to give deoxythymidine phosphate, and 17ß-estradiol (E2) induces TS gene expression in MCF-7 human breast cancer cells. Analysis of the TS gene promoter showed that E2-responsiveness required the -229 to -140 promoter region containing a G-rich sequence and CACCC box. Subsequent mutational analysis of this region indicated that only the G-rich motif (-150 to -142) was required for E2 action. Results of gel mobility shift and in vitro DNA footprinting assays showed that both estrogen receptor {alpha} (ER{alpha}) and Sp1 proteins were required for hormone-induced trans-activation that involved ER{alpha}/Sp1 binding to the G-rich site in which only Sp1 protein bound DNA. Both proteins also interacted in Drosophila cells in functional assays, confirming the transcriptional activation of TS-involved ER{alpha}/Sp1, and this adds to the increasing number of genes that are activated through this pathway in breast cancer cells.




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