Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells.
Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells.
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雌激素受体沉默可诱导人乳腺癌细胞上皮细胞向间质细胞的转变。
DOI：
10.1371/journal.pone.0020610
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Luqmani YA
中科院分区：
文献类型：
--
作者：
Al Saleh S;Al Mulla F;Luqmani YA
我们提出了这样的假设，即雌激素受体功能的丧失导致乳腺癌的内分泌抵抗，也导致从上皮细胞到间充质细胞表型的转分化，这是增加侵袭性和转移倾向的原因。siRNA介导的MCF 7乳腺癌细胞中雌激素受体的沉默导致雌激素/他莫昔芬抗性细胞（pII）具有改变的形态、增加的运动性以及从角蛋白/肌动蛋白到基于波形蛋白的细胞骨架的重排和转换，以及侵入细胞外基质的模拟组分的能力。使用Affytek Human Genome U133 plus 2.0 GeneChip进行的表型分析表明，约2500个可识别的独特序列的几何倍数变化≥3，其中约1270个在pII细胞中上调。这些变化与其产物参与细胞运动、细胞粘附丧失和与细胞外基质相互作用的基因有关。对数据的选择性分析还显示从腔细胞标记物到基底细胞标记物的转变，以及通常与间充质特征相关的广谱基因的表达增加，从而导致上皮特异性标记物的丢失。几种肽生长因子及其受体的过表达表明对pII细胞的较高增殖速率的贡献增加，以及有助于其转移活性的潜力。已被确定为上皮细胞向间充质细胞转化的关键转录驱动因子的信号分子也被发现在pII细胞中升高。这些数据支持了我们的假设，即在以前的雌激素/抗雌激素敏感细胞中诱导的雌激素受体的丧失是伴随的内分泌依赖性丧失和一系列可能的平行事件的发生的触发因素，这些事件将细胞从上皮细胞改变为间充质细胞类型。通过靶向特定介质抑制这种转变可能提供一种有用的补充策略，以规避内分泌敏感性丧失的影响。
We propose the hypothesis that loss of estrogen receptor function which leads to endocrine resistance in breast cancer, also results in trans-differentiation from an epithelial to a mesenchymal phenotype that is responsible for increased aggressiveness and metastatic propensity. siRNA mediated silencing of the estrogen receptor in MCF7 breast cancer cells resulted in estrogen/tamoxifen resistant cells (pII) with altered morphology, increased motility with rearrangement and switch from a keratin/actin to a vimentin based cytoskeleton, and ability to invade simulated components of the extracellular matrix. Phenotypic profiling using an Affymetrix Human Genome U133 plus 2.0 GeneChip indicated geometric fold changes ≥3 in approximately 2500 identifiable unique sequences, with about 1270 of these being up-regulated in pII cells. Changes were associated with genes whose products are involved in cell motility, loss of cellular adhesion and interaction with the extracellular matrix. Selective analysis of the data also showed a shift from luminal to basal cell markers and increased expression of a wide spectrum of genes normally associated with mesenchymal characteristics, with consequent loss of epithelial specific markers. Over-expression of several peptide growth factors and their receptors are indicative of an increased contribution to the higher proliferative rates of pII cells as well as aiding their potential for metastatic activity. Signalling molecules that have been identified as key transcriptional drivers of epithelial to mesenchymal transition were also found to be elevated in pII cells. These data support our hypothesis that induced loss of estrogen receptor in previously estrogen/antiestrogen sensitive cells is a trigger for the concomitant loss of endocrine dependence and onset of a series of possibly parallel events that changes the cell from an epithelial to a mesenchymal type. Inhibition of this transition through targeting of specific mediators may offer a useful supplementary strategy to circumvent the effects of loss of endocrine sensitivity.
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DOI：
10.1073/pnas.0909333107
发表时间：
2010-01-19
影响因子：
11.1
作者：
Gjerdrum, Christine;Tiron, Crina;Lorens, James B.
通讯作者：
Lorens, James B.
影响因子：
8
作者：
Bindels, S.;Mestdagt, M.;Gilles, C.
通讯作者：
Gilles, C.
影响因子：
3
作者：
Eden, Eran;Navon, Roy;Yakhini, Zohar
通讯作者：
Yakhini, Zohar
影响因子：
4.7
作者：
Kim, Semi;Kang, Hee Young;Park, Young-Kyu
通讯作者：
Park, Young-Kyu
影响因子：
8
作者：
Charafe-Jauffret, E;Ginestier, C;Bertucci, F
通讯作者：
Bertucci, F