Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation
Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation
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DOI：
10.1073/pnas.1009575107
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发表时间：
2010-08-24
影响因子：
11.1
通讯作者：
Das, Gokul M.
中科院分区：
文献类型：
--
作者：
Konduri, Santhi D.;Medisetty, Rajesh;Das, Gokul M.
雌激素受体α (ER α)在乳腺癌的发生和发展中起着重要作用，而p53是主要的肿瘤抑制因子。我们之前报道过ER α与p53结合，导致p53的转录调节受到抑制。在这里，我们报告了ER α抑制p53的转激活功能的分子机制。序列ChIP实验表明，ER α通过募集核受体核心加压因子（NCoR和SMRT）和组蛋白去乙酰化酶1 (HDAC1)，抑制人乳腺癌细胞中p53介导的转录激活。rnai介导的NCoR下调导致内源性细胞周期蛋白依赖性激酶（CDK）抑制剂p21(Waf1/Cip1) （CDKN1A）基因的表达增加，该基因是p53的一个原型转录靶点。17 -雌二醇（E2）增强了ER α与p53的结合并抑制了p21的转录，而抗雌激素则减少了ER α的募集并诱导了转录。雌激素和抗雌激素对p21转录的影响与已知的对常规含有ere的ER α靶基因pS2/TFF1的影响截然相反。这些结果表明，ER α通过双重策略促进异常细胞增殖：增强含有ere的促增殖基因的转录和抑制p53应答的抗增殖基因的转录。重要的是，ER α与p53结合并抑制含有干细胞/祖细胞的小鼠乳腺球中p53的转录激活，这表明ER-p53相互作用在乳腺组织稳态和癌症形成中可能起作用。此外，回顾性研究分析了表达野生型或突变型p53的er阳性乳腺癌患者对他莫昔芬治疗的反应，表明野生型p53的存在是阳性治疗反应的重要决定因素。
Estrogen receptor alpha (ER alpha) plays an important role in the onset and progression of breast cancer, whereas p53 functions as a major tumor suppressor. We previously reported that ER alpha binds to p53, resulting in inhibition of transcriptional regulation by p53. Here, we report on the molecular mechanisms by which ER alpha suppresses p53's transactivation function. Sequential ChIP assays demonstrated that ER alpha represses p53-mediated transcriptional activation in human breast cancer cells by recruiting nuclear receptor core-pressors (NCoR and SMRT) and histone deacetylase 1 (HDAC1). RNAi-mediated down-regulation of NCoR resulted in increased endogenous expression of the cyclin-dependent kinase (CDK)inhibitor p21(Waf1/Cip1) (CDKN1A) gene, a prototypic transcriptional target of p53. While 17 beta-estradiol (E2) enhanced ER alpha binding to p53 and inhibited p21 transcription, antiestrogens decreased ER alpha recruitment and induced transcription. The effects of estrogen and antiestrogens on p21 transcription were diametrically opposite to their known effects on the conventional ERE-containing ER alpha target gene, pS2/TFF1. These results suggest that ER alpha uses dual strategies to promote abnormal cellular proliferation: enhancing the transcription of ERE-containing proproliferative genes and repressing the transcription of p53-responsive antiproliferative genes. Importantly, ER alpha binds to p53 and inhibits transcriptional activation by p53 in stem/progenitor cell-containing murine mammospheres, suggesting a potential role for the ER-p53 interaction in mammary tissue homeostasis and cancer formation. Furthermore, retrospective studies analyzing response to tamoxifen therapy in a subset of patients with ER-positive breast cancer expressing either wild-type or mutant p53 suggest that the presence of wild-type p53 is an important determinant of positive therapeutic response.