ERα as ligand-independent activator of CDH-1 regulates determination and maintenance of epithelial morphology in breast cancer cells
ERα as ligand-independent activator of CDH-1 regulates determination and maintenance of epithelial morphology in breast cancer cells
复制标题
DOI：
10.1073/pnas.0903033106
复制
发表时间：
2009-05-05
影响因子：
11.1
通讯作者：
De Bortoli, Michele
中科院分区：
文献类型：
--
作者：
Cardamone, Maria Dafne;Bardella, Chiara;De Bortoli, Michele
雌激素受体α（ER α）和E-钙粘蛋白是管腔上皮乳腺癌细胞的主要标志物，E-钙粘蛋白是上皮表型的主要看护者。E-钙粘蛋白抑制是癌细胞获得运动和侵袭特性所必需的，并且已知在ER阳性乳腺癌细胞中，雌激素下调E-钙粘蛋白基因转录。我们在这里报告，ER α是结合到E-钙粘蛋白启动子在存在和完全不存在雌激素，这表明一个意想不到的作用，unliganded ER α在E-钙粘蛋白转录。事实上，我们的数据表明，激活unliganded ER α和抑制雌激素激活ER α需要直接结合到一个半雌激素反应元件内的E-钙粘蛋白启动子和相关的辅激活子的辅阻遏物的交换。因此，这些结果表明未配体的ER α在控制乳腺癌细胞中上皮表型的基本看护者中具有关键作用。在这里，我们表明，ER α阳性乳腺癌T47 D细胞转导sfRON激酶经历了一个完整的上皮间充质转化和失去E-钙粘蛋白和ER α表达。我们的数据表明，虽然E-钙粘蛋白基因变得高甲基化和异染色质，激酶抑制剂可以恢复E-钙粘蛋白的表达，连同上皮细胞的形态在ER α依赖的方式。类似地，在不存在配体的情况下，ER α的转染足以恢复sfRON-T47 D和其他ER α-、E-钙粘蛋白阴性细胞中的E-钙粘蛋白转录。因此，我们的研究结果表明，ER α在乳腺癌细胞中发挥着配体非依赖性激活剂和配体依赖性E-钙粘蛋白抑制剂的双重作用。
Estrogen receptor alpha (ER alpha) and E-cadherin are primary markers of luminal epithelial breast cancer cells with E-cadherin being a main caretaker of the epithelial phenotype. E-cadherin repression is needed for cancer cells to acquire motile and invasive properties, and it is known that in ER-positive breast cancer cells, estrogen down-regulate E-cadherin gene transcription. We report here that ER alpha is bound to the E-cadherin promoter in both the presence and the complete absence of estrogen, suggesting an unexpected role for unliganded ER alpha in E-cadherin transcription. Indeed, our data reveal that activation by unliganded ER alpha and repression by estrogen-activated ER alpha require direct binding to a half-estrogen response element within the E-cadherin promoter and exchange from associated coactivators to corepressors. Therefore, these results suggest a pivotal role for unliganded ER alpha in controlling a fundamental caretaker of the epithelial phenotype in breast cancer cells. Here, we show that ER alpha-positive breast cancer T47D cells transduced with the sfRON kinase undergo a full epithelial mesenchymal conversion and lose E-cadherin and ER alpha expression. Our data show that, although the E-cadherin gene becomes hypermethylated and heterochromatic, kinase inhibitors can restore E-cadherin expression, together with an epithelial morphology in an ER alpha-dependent fashion. Similarly, transfection of ER alpha, in the absence of ligands, was sufficient to restore E-cadherin transcription in both sfRON-T47D and other ER alpha-, E-cadherin-negative cells. Therefore, our results suggest a novel role for the ER alpha that plays the dual role of ligand-independent activator and ligand-dependent repressor of E-cadherin in breast cancer cells.