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TFAP2C Controls Hormone Response in Breast Cancer Cells through Multiple Pathways of Estrogen Signaling

¹ Department of Surgery and Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, Iowa and ² Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Ronald J. Weigel, Department of Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, 1516 JCP, Iowa City, IA 52242-1086. Phone: 319-353-7474; Fax: 319-356-8378; E-mail: Ronald-Weigel{at}uiowa.edu.

Breast cancers expressing estrogen receptor- (ER) are associated with a favorable biology and are more likely to respond to hormonal therapy. In addition to ER, other pathways of estrogen response have been identified including ERß and GPR30, a membrane receptor for estrogen, and the key mechanisms regulating expression of ERs and hormone response remain controversial. Herein, we show that TFAP2C is the key regulator of hormone responsiveness in breast carcinoma cells through the control of multiple pathways of estrogen signaling. TFAP2C regulates the expression of ER directly by binding to the ER promoter and indirectly via regulation of FoxM1. In so doing, TFAP2C controls the expression of ER target genes, including pS2, MYB, and RERG. Furthermore, TFAP2C controlled the expression of GPR30. In distinct contrast, TFAP2A, a related factor expressed in breast cancer, was not involved in estrogen-mediated pathways but regulated expression of genes controlling cell cycle arrest and apoptosis including p21^CIP1 and IGFBP-3. Knockdown of TFAP2C abrogated the mitogenic response to estrogen exposure and decreased hormone-responsive tumor growth of breast cancer xenografts. We conclude that TFAP2C is a central control gene of hormone response and is a novel therapeutic target in the design of new drug treatments for breast cancer. [Cancer Res 2007;67(18):8439–43]