Comparative Oncology Laboratory, University of California, Davis, CA 95616, USA.
J Biol Chem. 2012 Aug 31;287(36):30117-27. doi: 10.1074/jbc.M112.367326. Epub 2012 Jul 11.
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 ERα. 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 ERα, 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 ERα. Specifically, we found that knockdown of ERα decreases expression of p53 and its downstream targets, MDM2 and p21. In addition, we found that ERα activates p53 transcription via binding to estrogen response element half-sites within the p53 promoter. Moreover, we found that loss of ERα desensitizes, whereas ectopic expression of ERα 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 ERα and p53 and a biological role of p53 in the DNA damage response in ER-positive breast cancers.
针对遗传毒性应激，p53 肿瘤抑制因子会诱导细胞周期停滞、细胞凋亡和 DNA 修复的靶基因。尽管 p53 是所有人类癌症中最常见的突变基因，但它仅在大约 20%的乳腺癌中发生突变。70%的乳腺癌病例为雌激素受体 (ER)-阳性并表达 ERα。ER 阳性乳腺癌通常预示着患者预后良好，对他莫昔芬等抗雌激素药物治疗有反应。然而，ER 阳性乳腺癌患者可能会经历 ERα 的缺失或减少，这与肿瘤生长侵袭性增加、预后不良以及 p53 功能丧失有关。与这一现象一致，我们发现 p53 是 ERα 的靶基因。具体而言，我们发现 ERα 的敲低会降低 p53 及其下游靶基因 MDM2 和 p21 的表达。此外，我们发现 ERα 通过与 p53 启动子内的 p53 启动子半位点结合来激活 p53 转录。此外，我们发现 ERα 的缺失会使乳腺癌细胞对 DNA 损伤诱导的生长抑制产生耐药性，而 ERα 的异位表达则以 p53 依赖性方式使乳腺癌细胞对其敏感。总之，这项研究深入了解了 ERα 和 p53 之间的反馈回路以及 p53 在 ER 阳性乳腺癌中 DNA 损伤反应中的生物学作用。
