ERα directly activated the MDR1 transcription to increase paclitaxel-resistance of ERα-positive breast cancer cells in vitro and in vivo
ERα directly activated the MDR1 transcription to increase paclitaxel-resistance of ERα-positive breast cancer cells in vitro and in vivo
复制标题
ERα直接激活MDR1转录以增加ERα阳性乳腺癌细胞体内外的紫杉醇耐药性。
DOI：
10.1016/j.biocel.2014.04.016
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发表时间：
2014-08-01
影响因子：
4
通讯作者：
Sun, Yu-Jie
中科院分区：
文献类型：
--
作者：
Shi, Jun-Feng;Yang, Nan;Sun, Yu-Jie
化疗通常用于治疗手术前或手术后的早期浸润性和晚期乳腺癌。越来越多的临床分析和体外研究表明，ER阳性乳腺癌细胞对化疗不敏感。彻底了解ER α如何介导耐药性是提高化疗疗效的先决条件。MDR 1基因编码的P-糖蛋白（P-gp）的过度表达是导致耐药的主要原因之一。ER与MDR 1在乳腺癌中的相关性尚不清楚，有限的报道相互矛盾。本研究从分子水平系统地探讨了ER α（+）乳腺癌细胞系和小鼠模型中ER α与P-gp过表达之间的内在联系。我们的数据显示，ER α通过与ERE 1/2结合并与Sp1相互作用激活MCF-7/PTX乳腺癌细胞中的MDR 1转录，Sp1桥接到MDR 1启动子内的下游富含CG的元件。MDR 1的敲除抑制了ER对MCF-7细胞的作用，并使细胞对紫杉醇敏感。选择性抑制ER α的ICI 182，780治疗显著降低了MDR 1表达，并增加了耐药乳腺癌细胞和异种移植肿瘤对紫杉醇的敏感性。我们的数据有力地证明了ER α能够通过激活MDR 1转录来增加乳腺癌细胞的耐药性。这一新的机制为ER α信号通路如何调节ER α（+）乳腺肿瘤对化疗的反应提供了新的见解，这可能会在未来开发新的乳腺癌治疗策略。(C)2014爱思唯尔有限公司版权所有。
Chemotherapy is commonly used to treat early-stage invasive and advanced-stage breast cancer either before or after surgery. Increasing evidence from clinical analysis and in vitro studies has shown that ER-positive breast cancer cells are insensitive to chemotherapy. Complete understanding of how ER alpha mediates drug resistance is prerequisite to improvement of the chemotherapeutic efficacy. Overexpression of P-glycoprotein (P-gp) encoded by MDR1 gene is one of the major causes of drug resistance. The association between ER and MDR1 in breast cancer is still unclear and the limited reports are conflict. This study systematically explored intrinsic link between ER alpha and the P-gp over-expression in paclitaxel-resistant ER alpha(+) breast cancer cell lines and mouse model in molecular details. Our data showed that ER alpha activated the MDR1 transcription in MCF-7/PTX breast cancer cells by binding to ERE1/2 and interacting with Sp1 that bridged to the downstream CG-rich element within the MDR1 promoter. Knockdown of MDR1 restrained the effect of ER in MCF-7 cells and sensitized the cells to paclitaxel. Treatment of ICI 182,780 that selectively suppressed ER alpha significantly decreased the MDR1 expression and increased the sensitivity of drug resistant breast cancer cells and xenograft tumors to paclitaxel. Our data strongly demonstrated that ER alpha was able to increase drug resistance of breast cancer cells through activating MDR1 transcription. This novel mechanism provides new insight to how the ER alpha signaling regulates response of ER alpha(+) breast tumors to chemotherapy, which may be exploited for developing novel therapeutic strategies for breast cancer in the future. (C) 2014 Elsevier Ltd. All rights reserved.