TLE1 is an anoikis regulator and is downregulated by Bit1 in breast cancer cells.
TLE1 is an anoikis regulator and is downregulated by Bit1 in breast cancer cells.
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DOI：
10.1158/1541-7786.mcr-12-0144
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Ruoslahti E
中科院分区：
文献类型：
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作者：
Brunquell C;Biliran H;Jennings S;Ireland SK;Chen R;Ruoslahti E
TLE1是一种与Groucho相关的转录抑制蛋白，在多种细胞系统中发挥生存和抗凋亡功能，并与癌症的发病机制有关。在本研究中，我们发现TLE1是正常乳腺上皮细胞和乳腺癌细胞中anoikis的调节因子。未转化的乳腺上皮细胞MCF10A细胞失去与细胞外基质（anoikis）的附着后诱导凋亡与TLE1表达的显著下调有关。这些细胞中外源性TLE1的强制表达促进了对anoikis的抗性。在乳腺癌细胞中，TLE1的表达在脱离ECM后显著上调。通过过表达和下调途径对TLE1表达的基因操作表明，TLE1促进乳腺癌细胞的抗瘤性和非锚定生长。从机制上讲，我们发现TLE1通过减少促凋亡Bit1-AES复合物的形成来抑制Bit1凋亡途径，部分原因是通过在细胞核中隔离AES。在失活过程中，线粒体释放Bit1以及细胞质定位Bit1或其细胞死亡结构域（CDD）的外源表达诱导细胞质易位和核TLE1蛋白降解。这些发现表明TLE1在维持乳腺癌细胞耐药中具有新的作用。这一结论得到了乳腺癌组织阵列免疫组化分析的支持，该分析表明，相对于非浸润性导管原位癌（DCIS）和正常乳腺上皮组织，TLE1在浸润性乳腺肿瘤中选择性上调。
TLE1 is a Groucho related transcriptional repressor protein that exerts survival and anti-apoptotic function in several cellular systems and has been implicated in the pathogenesis of cancer. In the present study, we found that TLE1 is a regulator of anoikis in normal mammary epithelial and breast carcinoma cells. The induction of apoptosis following loss of cell attachment to the extracellular matrix (anoikis) in untransformed mammary epithelial MCF10A cells was associated with significant downregulation of TLE1 expression. Forced expression of exogenous TLE1 in these cells promoted resistance to anoikis. In breast cancer cells, TLE1 expression was significantly upregulated following detachment from the ECM. Genetic manipulation of TLE1 expression via overexpression and downregulation approaches indicated that TLE1 promotes the anoikis resistance and anchorage-independent growth of breast carcinoma cells. Mechanistically, we show that TLE1 inhibits the Bit1 anoikis pathway by reducing the formation of the pro-apoptotic Bit1-AES complex in part through sequestration of AES in the nucleus. The mitochondrial release of Bit1 during anoikis as well as exogenous expression of the cytoplasmic localized Bit1 or its cell death domain (CDD) induced cytoplasmic translocation and degradation of nuclear TLE1 protein. These findings indicate a novel role for TLE1 in the maintenance of anoikis resistance in breast cancer cells. This conclusion is supported by an immunohistochemical analysis of a breast cancer tissue array illustrating that TLE1 is selectively upregulated in invasive breast tumors relative to noninvasive ductal carcinoma in situ (DCIS) and normal mammary epithelial tissues.