ERα signaling through slug regulates E-cadherin and EMT
ERα signaling through slug regulates E-cadherin and EMT
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DOI：
10.1038/onc.2009.433
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发表时间：
2010-03-01
期刊：
影响因子：
8
通讯作者：
Barsky, S. H.
中科院分区：
文献类型：
--
作者：
Ye, Y.;Xiao, Y.;Barsky, S. H.
ER α信号通路是人类乳腺癌中最重要和研究最多的通路之一，但仍存在许多问题，例如对乳腺癌有反应的癌症如何发展为更具侵袭性和乳腺癌独立表型。我们已经注意到，人类乳腺癌表现出很强的直接相关性ER α和E-cadherin表达的免疫组化，这表明ER α信号可能调节E-cadherin，并暗示这种调节可能影响上皮间质转化（EMT）和肿瘤的进展。为了研究这一假设及其背后的机制，我们研究了ER α转染的ER α阴性乳腺癌细胞系MDA-MB-468和MDA-MB-231中ER α信号传导的作用，以及ER α敲低在天然表达ER α阳性细胞系MCF-7和T47 D中的作用。当ER α在ER α阴性细胞系中过表达时，17 β-雌二醇（E2）减少了蛞蝓，增加了E-钙粘蛋白。最大限度地表现出这些变化的克隆更多地生长在团块中，并且在基质胶中变得不那么具有侵袭性。当ER α在ER α阳性细胞系中被敲低时，slug增加，E-cadherin减少，细胞变得细长并表现出增加的Matrigel侵袭。ER α信号通过两种不同的机制降低slug表达：直接，通过配体激活的ER α、HDAC抑制剂（HDAC 1）和核受体辅阻遏物（N-CoR）的辅阻遏物复合物的形成抑制slug转录，所述辅阻遏物复合物在三个半位点雌激素反应元件（ERE）中结合slug启动子;间接通过磷酸肌醇3-激酶（PI 3 K）/蛋白激酶B（Akt）磷酸化和GSK-3 β失活。GSK-3 β失活反过来又抑制了蛞蝓的表达并增加了E-钙粘蛋白。在人类乳腺癌病例中，蛞蝓与ER α和E-cadherin免疫反应性之间存在强烈的负相关。我们的研究结果表明，ER α信号通过蛞蝓调节E-cadherin和EMT。Oncogene（2010）29，1451-1462; doi：10.1038/onc.2009.433; 2010年1月18日在线发表
The ER alpha signaling pathway is one of the most important and most studied pathways in human breast cancer, yet numerous questions still exist such as how hormonally responsive cancers progress to a more aggressive and hormonally independent phenotype. We have noted that human breast cancers exhibit a strong direct correlation between ER alpha and E-cadherin expression by immunohistochemistry, suggesting that ER alpha signaling might regulate E-cadherin and implying that this regulation might influence epithelial-mesenchymal transition (EMT) and tumor progression. To investigate this hypothesis and the mechanisms behind it, we studied the effects of ER alpha signaling in ER alpha-transfected ER alpha-negative breast carcinoma cell lines, the MDA-MB-468 and the MDA-MB-231 and the effects of ER alpha knockdown in naturally expressing ER alpha-positive lines, MCF-7 and T47D. When ER alpha was overexpressed in the ER alpha-negative lines, 17 beta-estradiol (E2) decreased slug and increased E-cadherin. Clones maximally exhibiting these changes grew more in clumps and became less invasive in Matrigel. When ER alpha was knocked down in the ER alpha-positive lines, slug increased, E-cadherin decreased, cells became spindly and exhibited increased Matrigel invasion. ER alpha signaling decreased slug expression by two different mechanisms: directly, by repression of slug transcription by the formation of a corepressor complex of ligand-activated ER alpha, HDAC inhibitor (HDAC1), and nuclear receptor corepressor (N-CoR) that bound the slug promoter in three half-site estrogen response elements (EREs); indirectly by phosphorylation and inactivation of GSK-3 beta through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt). The GSK-3 beta inactivation, in turn, repressed slug expression and increased E-cadherin. In human breast cancer cases, there was a strong inverse correlation between slug and ER alpha and E-cadherin immunoreactivity. Our findings indicate that ER alpha signaling through slug regulates E-cadherin and EMT. Oncogene (2010) 29, 1451-1462; doi:10.1038/onc.2009.433; published online 18 January 2010