Woodfield George W, Horan Annamarie D, Chen Yizhen, Weigel Ronald J
Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242-1086, USA.
Cancer Res. 2007 Sep 15;67(18):8439-43. 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.
表达雌激素受体α（ERα）的乳腺癌具有良好的生物学特性，且更有可能对激素治疗产生反应。除了ERα，还发现了雌激素反应的其他途径，包括ERβ和雌激素的膜受体GPR30，而调节ERs表达和激素反应的关键机制仍存在争议。在此，我们表明TFAP2C通过控制雌激素信号传导的多种途径，是乳腺癌细胞中激素反应性的关键调节因子。TFAP2C通过与ERα启动子结合直接调节ERα的表达，并通过调节FoxM1间接调节。通过这样做，TFAP2C控制ERα靶基因的表达，包括pS2、MYB和RERG。此外，TFAP2C控制GPR30的表达。与之形成鲜明对比的是，在乳腺癌中表达的相关因子TFAP2A不参与雌激素介导的途径，但调节控制细胞周期停滞和凋亡的基因的表达，包括p21（CIP1）和IGFBP-3。敲低TFAP2C消除了对雌激素暴露的促有丝分裂反应，并降低了乳腺癌异种移植瘤的激素反应性肿瘤生长。我们得出结论，TFAP2C是激素反应的核心控制基因，是乳腺癌新药治疗设计中的一个新的治疗靶点。
