TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 18; pp. 8439 - 8443
• Main Authors: WOODFIELD, George W, HORAN, Annamarie D, YIZHEN CHEN, WEIGEL, Ronald J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2007
• Subjects: Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Growth Processes - drug effects; Cell Growth Processes - physiology; Cell Line, Tumor; Estradiol - pharmacology; Estrogen Receptor alpha - biosynthesis; Estrogen Receptor alpha - genetics; Estrogens - metabolism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Neoplasms, Hormone-Dependent - genetics; Neoplasms, Hormone-Dependent - metabolism; Neoplasms, Hormone-Dependent - pathology; Pharmacology. Drug treatments; Promoter Regions, Genetic; RNA, Small Interfering - genetics; Signal Transduction; Transcription Factor AP-2 - biosynthesis; Transcription Factor AP-2 - genetics; Transcription Factor AP-2 - metabolism; Transfection; Tumors; Mammary gland diseases; Signal transduction; Signaling pathway; Estrogen; Breast cancer; Malignant tumor; Sex steroid hormone; Ovarian hormone; Tumor cell
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-2293

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.