Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells
Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells
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DOI：
10.1016/j.matbio.2015.02.008
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发表时间：
2015-04-01
期刊：
影响因子：
6.9
通讯作者：
Karamanos, Nikos K.
中科院分区：
文献类型：
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作者：
Bouris, Panagiotis;Skandalis, Spyros S.;Karamanos, Nikos K.
17 β-雌二醇（E2）/雌激素受体α（ER α）信号通路是乳腺癌中最重要的通路之一。E2在癌细胞生长、存活和结构以及基因表达调控机制中起着关键作用。在这项研究中，我们建立了稳定转染的MCF-7细胞，通过敲低ER α基因（指定为MCF-7/SP10 +细胞），使用特定的shRNA慢病毒颗粒，并将它们与对照细胞（MCF-7/c）进行比较。有趣的是，MCF-7细胞中的ER α沉默强烈诱导细胞表型变化，伴随着上皮向间充质转化（EMT）的几种典型标志物的基因和蛋白质表达的显著变化。值得注意的是，这些细胞表现出增强的细胞增殖、迁移和侵袭。此外，ER α抑制强烈影响EGFR和HER 2受体酪氨酸激酶的基因和蛋白表达，以及各种细胞外基质（ECM）效应物，包括基质金属蛋白酶及其内源性抑制剂（MMP/TIMP）和纤溶酶原激活系统的组分。在ER α缺乏的MCF-7/SP 10+细胞中，E2对MCF-7/c细胞中HER 2、MT 1-MMP、MMP 1、MMP 9、uPA、tPA和派-1表达的作用被消除。这些数据表明，E2/ER α途径的调节作用，在胞外蛋白水解分子网络的组成和活性。值得注意的是，ER α的缺失通过诱导某些基质大分子表达水平的变化来促进乳腺癌细胞的迁移和侵袭（尤其是uPA、tPA、派-1）通过EGFR-ERK信号通路。乳腺癌细胞中ER α的缺失导致有效的EMT，其特征在于特异性基质大分子表达谱的显著变化，突出了基质效应物在乳腺癌中的潜在节点作用。乳腺癌内分泌抵抗(C)2015年由Elsevier B. V.出版
The 17 beta-estradiol (E2)/estrogen receptor alpha (ER alpha) signaling pathway is one of the most important pathways in hormone-dependent breast cancer. E2 plays pivotal roles in cancer cell growth, survival, and architecture as well as in gene expression regulatory mechanisms. In this study, we established stably transfected MCF-7 cells by knocking down the ER alpha gene (designated as MCF-7/SP10 + cells), using specific shRNA lentiviral particles, and compared them with the control cells (MCF-7/c). Interestingly, ERa silencing in MCF-7 cells strongly induced cellular phenotypic changes accompanied by significant changes in gene and protein expression of several markers typical of epithelial to mesenchymal transition (EMT). Notably, these cells exhibited enhanced cell proliferation, migration and invasion. Moreover, ERa suppression strongly affected the gene and protein expression of EGFR and HER2 receptor tyrosine kinases, and various extracellular matrix (ECM) effectors, including matrix metalloproteinases and their endogenous inhibitors (MMPs/TIMPs) and components of the plasminogen activation system. The action caused by E2 in MCF-7/c cells in the expression of HER2, MT1-MMP, MMP1, MMP9, uPA, tPA, and PAI-1 was abolished in MCF-7/SP10 + cells lacking ERa. These data suggested a regulatory role for the E2/ER alpha pathway in respect to the composition and activity of the extracellular proteolytic molecular network. Notably, loss of ER alpha promoted breast cancer cell migration and invasion by inducing changes in the expression levels of certain matrix macromolecules (especially uPA, tPA, PAI-1) through the EGFR-ERK signaling pathway.In conclusion, loss of ERa in breast cancer cells results in a potent EMT characterized by striking changes in the expression profile of specific matrix macromolecules highlighting the potential nodal role of matrix effectors in breast cancer endocrine resistance. (C) 2015 Published by Elsevier B.V.