Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Biochem Biophys Res Commun. 2012 Oct 12;427(1):47-53. doi: 10.1016/j.bbrc.2012.08.144. Epub 2012 Sep 10.
Estrogen receptors (ER) are expressed in approximately 65% of human breast cancer. Clinical trials and retrospective analyses showed that ER-positive (ER+) tumors were more vulnerable to development of chemotherapy resistance than ER-negative (ER-) tumors. The underlying mechanism is still to be elucidated. Aberrant DNA methylation has been recognized to be associated with cancer chemotherapy resistance. Recently, steroid hormone and their receptors have been found to be involved in the regulation of methyltransferases (DNMTs) and thereby contribute to chemotherapy resistance. The purpose of this study is to explore whether ERα could directly regulate the DNMTs expression. We first analyzed the methylation alterations and its correlation with the expression levels of three types of DNMTs in our established paclitaxel-resistant breast cancer lines, MCF-7(ER+)/PTX and MDA-MB-231(ER-)/PTX cell lines, using qMSP, real-time PCR and Western blot. Then we determined the function of ERα in regulation of DNMT1 using luciferase report gene systems. Our data demonstrated for the first time that ERα could upregulate DNMT1 expression by directly binding to the DNMT1 promoter region in MFC-7(ER+)/PTX cells.
雌激素受体（ER）在大约 65%的人类乳腺癌中表达。临床试验和回顾性分析表明，ER 阳性（ER+）肿瘤比 ER 阴性（ER-）肿瘤更容易产生化疗耐药性。其潜在机制仍有待阐明。异常的 DNA 甲基化已被认为与癌症化疗耐药性有关。最近，甾体激素及其受体被发现参与调节甲基转移酶（DNMTs），从而导致化疗耐药性。本研究旨在探讨 ERα 是否可以直接调节 DNMTs 的表达。我们首先使用 qMSP、实时 PCR 和 Western blot 分析了我们建立的紫杉醇耐药乳腺癌细胞系 MCF-7（ER+）/PTX 和 MDA-MB-231（ER-）/PTX 中三种类型的 DNMTs 的甲基化改变及其与表达水平的相关性。然后，我们使用荧光素酶报告基因系统确定了 ERα 在调节 DNMT1 中的功能。我们的数据首次表明，ERα 可以通过直接结合 MFC-7（ER+）/PTX 细胞中的 DNMT1 启动子区域来上调 DNMT1 的表达。
