TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling.
Breast cancers expressing estrogen receptor-alpha (ERalpha) are associated with a favorable biology and are more likely to respond to hormonal therapy. In addition to ERalpha, other pathways of estrogen response have been identified including ERbeta 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 ERalpha directly by binding to the ERalpha promoter and indirectly via regulation of FoxM1. In so doing, TFAP2C controls the expression of ERalpha 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.
Woodfield
George W
GW
Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242-1086, USA.
Horan
Annamarie D
AD
Chen
Yizhen
Y
Weigel
Ronald J
RJ
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D004967:Estrogens / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D050656:Transcription Factor AP-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D047628:Estrogen Receptor alpha; D004967:Estrogens; D034741:RNA, Small Interfering; C493679:TFAP2C protein, human; D050656:Transcription Factor AP-2; D004958:Estradiol