p53, a Target of Estrogen Receptor (ER) α, Modulates DNA Damage-induced Growth Suppression in ER-positive Breast Cancer Cells
p53, a Target of Estrogen Receptor (ER) α, Modulates DNA Damage-induced Growth Suppression in ER-positive Breast Cancer Cells
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DOI：
10.1074/jbc.m112.367326
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发表时间：
2012-08-31
影响因子：
4.8
通讯作者：
Chen, Xinbin
中科院分区：
文献类型：
--
作者：
Berger, Crystal E.;Qian, Yingjuan;Chen, Xinbin
作为对遗传毒性应激的反应，p53肿瘤抑制因子诱导细胞周期停滞、凋亡和DNA修复的靶基因。虽然p53是所有人类癌症中最常见的突变基因，但它仅在约20%的乳腺癌中发生突变。所有乳腺癌病例中的70%是雌激素受体（ER）阳性并表达ER α。ER阳性乳腺癌通常表明患者预后良好，对抗雌激素（如他莫昔芬）的治疗反应性良好。然而，ER阳性乳腺癌患者可能会经历ER α的丢失或减少，这与侵袭性肿瘤生长，侵袭性增加，预后不良和p53功能丧失有关。与此一致，我们发现p53是ER α的靶基因。具体来说，我们发现ER α的敲低降低了p53及其下游靶点MDM2和p21的表达。此外，我们发现ER α通过与p53启动子内的雌激素反应元件半位点结合来激活p53转录。此外，我们发现ER α的缺失使乳腺癌细胞对DNA损伤诱导的生长抑制以p53依赖的方式脱敏，而ER α的异位表达使乳腺癌细胞对DNA损伤诱导的生长抑制敏感。总之，这项研究提供了一个深入了解ER α和p53之间的反馈回路和p53在ER阳性乳腺癌中的DNA损伤反应的生物学作用。
In response to genotoxic stress, the p53 tumor suppressor induces target genes for cell cycle arrest, apoptosis, and DNA repair. Although p53 is the most commonly mutated gene in all human cancers, it is only mutated in about 20% of breast cancers. 70% of all breast cancer cases are estrogen receptor (ER)positive and express ER alpha. ER-positive breast cancer generally indicates good patient prognosis and treatment responsiveness with antiestrogens, such as tamoxifen. However, ER-positive breast cancer patients can experience loss or a reduction in ER alpha, which is associated with aggressive tumor growth, increased invasiveness, poor prognosis, and loss of p53 function. Consistent with this, we found that p53 is a target gene of ER alpha. Specifically, we found that knockdown of ER alpha decreases expression of p53 and its downstream targets, MDM2 and p21. In addition, we found that ER alpha activates p53 transcription via binding to estrogen response element half-sites within the p53 promoter. Moreover, we found that loss of ER alpha desensitizes, whereas ectopic expression of ER alpha sensitizes, breast cancer cells to DNA damage-induced growth suppression in a p53-dependent manner. Altogether, this study provides an insight into a feedback loop between ER alpha and p53 and a biological role of p53 in the DNA damage response in ER-positive breast cancers.