TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling
TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling
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DOI：
10.1158/0008-5472.can-07-2293
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发表时间：
2007-09-15
期刊：
影响因子：
11.2
通讯作者：
Weigel, Ronald J.
中科院分区：
文献类型：
--
作者：
Woodfield, George W.;Horan, Annamarie D.;Weigel, Ronald J.
表达雌激素受体α（ER α）的乳腺癌与有利的生物学相关，并且更可能对激素治疗有反应。除ER α外，还发现了其他雌激素反应途径，包括ER β和GPR 30（雌激素的膜受体），调节ER表达和激素反应的关键机制仍存在争议。在此，我们发现TFAP 2C是乳腺癌细胞中激素反应性的关键调节因子，通过控制多种雌激素信号传导途径。TFAP 2C通过与ER α启动子结合直接调节ER α的表达，并通过调节FoxM 1间接调节ER α的表达。在此过程中，TFAP 2C控制ER α靶基因的表达，包括pS2、AM和RERG。此外，TFAP 2C控制GPR 30的表达。与此形成鲜明对比的是，乳腺癌中表达的相关因子TFAP 2A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（包括p21（CIPI）和IGFBP-3）的表达。TFAP 2C的敲除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物的增殖反应性肿瘤生长。我们的结论是，TFAP 2C是一个中央控制基因的激素反应，是一个新的治疗靶点，在设计新的药物治疗乳腺癌。
Breast cancers expressing estrogen receptor-alpha (ER alpha) are associated with a favorable biology and are more likely to respond to hormonal therapy. In addition to ER alpha, other pathways of estrogen response have been identified including ER beta 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 alpha directly by binding to the ER alpha promoter and indirectly via regulation of FoxM1. In so doing, TFAP2C controls the expression of ER alpha target genes, including pS2, AM, 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(CIPI) 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.