Epithelial cell adhesion molecule promotes breast cancer resistance protein-mediated multidrug resistance in breast cancer by inducing partial epithelial-mesenchymal transition
Epithelial cell adhesion molecule promotes breast cancer resistance protein-mediated multidrug resistance in breast cancer by inducing partial epithelial-mesenchymal transition
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上皮细胞粘附分子通过诱导部分上皮-间质转化促进乳腺癌耐药蛋白介导的乳腺癌多药耐药
DOI：
10.1002/cbin.11598
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发表时间：
2021-04-01
影响因子：
3.9
通讯作者：
Hu, Xiao-ling
中科院分区：
文献类型：
--
作者：
Shi, Rui-Zan;He, Yi-Fan;Hu, Xiao-ling
乳腺癌耐药蛋白（BCRP）的过表达在乳腺癌获得性多药耐药（MDR）中起着至关重要的作用。阐明赋予BCRP介导的MDR的分子事件在乳腺癌中具有重要的治疗意义。上皮细胞粘附分子（EpCAM）与包括乳腺癌在内的各种类型癌症的肿瘤进展和耐药性有关。然而，EpCAM在乳腺癌中BCRP介导的MDR中的作用仍然未知。在本研究中，我们发现，在BCRP过表达的乳腺癌MCF-7/MX细胞中，EpCAM表达上调，使用siRNA敲低EpCAM降低BCRP表达，并增加MCF-7/MX细胞对米托蒽醌（MX）的敏感性。上皮间质转化（EMT）促进了乳腺癌细胞中BCRP介导的MDR，EpCAM敲低部分抑制了MCF-7/MX细胞中的EMT进展。此外，Wnt/β-连环蛋白信号在MCF-7/MX细胞中被激活，并且该信号的抑制减弱了EpCAM和BCRP表达并部分逆转了EMT。总之，这项研究表明，EpCAM上调Wnt/β-连环蛋白信号诱导部分EMT促进乳腺癌细胞中BCRP介导的MDR耐药。EpCAM可能是克服BCRP介导的乳腺癌耐药的潜在治疗靶点。
Overexpression of breast cancer resistance protein (BCRP) plays a crucial role in the acquired multidrug resistance (MDR) in breast cancer. The elucidation of molecular events that confer BCRP-mediated MDR is of major therapeutic importance in breast cancer. Epithelial cell adhesion molecule (EpCAM) has been implicated in tumor progression and drug resistance in various types of cancers, including breast cancer. However, the role of EpCAM in BCRP-mediated MDR in breast cancer remains unknown. In the present study, we revealed that EpCAM expression was upregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and EpCAM knockdown using siRNA reduced BCRP expression and increased the sensitivity of MCF-7/MX cells to mitoxantrone (MX). The epithelial-mesenchymal transition (EMT) promoted BCRP-mediated MDR in breast cancer cells, and EpCAM knockdown partially suppressed EMT progression in MCF-7/MX cells. In addition, Wnt/beta-catenin signaling was activated in MCF-7/MX cells, and the inhibition of this signaling attenuated EpCAM and BCRP expression and partially reversed EMT. Together, this study illustrates that EpCAM upregulation by Wnt/beta-catenin signaling induces partial EMT to promote BCRP-mediated MDR resistance in breast cancer cells. EpCAM may be a potential therapeutic target for overcoming BCRP-mediated resistance in human breast cancer.