Flotillins as regulators of ErbB2 levels in breast cancer
Flotillins as regulators of ErbB2 levels in breast cancer
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DOI：
10.1038/onc.2012.357
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发表时间：
2013-07-18
期刊：
影响因子：
8
通讯作者：
Sandvig, K.
中科院分区：
文献类型：
--
作者：
Pust, S.;Klokk, T. I.;Sandvig, K.
受体酪氨酸激酶ErbB 2的扩增和过表达发生在高达30%的人类乳腺癌中，并且高ErbB 2水平与乳腺癌患者的不良预后相关。与上皮生长因子受体（ErbB 1）相反，ErbB 2不受配体诱导机制的下调。在这里，我们表明，flotillin参与ErbB 2在质膜上的稳定。在SKBR 3乳腺癌细胞和乳腺癌组织中，可以证明flotilin和ErbB 2表达水平之间的正相关。此外，来自194名诊断为乳腺癌的患者的活检组织微阵列分析显示，flotillin-2成为乳腺癌预后的潜在预测因子。flotillin-1和flotillin-2的消耗导致ErbB 2的内化和降解。此外，发现flotillin-1和flotillin-2与ErbB 2和Hsp 90形成分子复合物。这些蛋白质之一的消耗导致该复合物的破坏，随后是ErbB 2在膜上的不稳定，以及其内化和降解。因此，ErbB 2触发的下游信号传导被抑制。我们的数据证明了一种干扰ErbB 2信号传导的新机制，这可能会产生临床影响。
Amplification and overexpression of the receptor tyrosine kinase ErbB2 occur in up to 30% of human breast cancers, and high ErbB2 levels are correlated with poor prognosis for breast cancer patients. In contrast to the epithelial growth factor receptor (ErbB1), ErbB2 is not downregulated by ligand-induced mechanisms. Here we show that flotillins are involved in the stabilization of ErbB2 at the plasma membrane. In SKBR3 breast cancer cells and breast cancer tissue, a positive correlation between flotillin and ErbB2 expression levels could be demonstrated. Moreover, the tissue microarray analyses of biopsies from 194 patients diagnosed with carcinomas of the breast showed that flotillin-2 emerged as a potential predictor of prognosis in breast cancer. Depletion of flotillin-1 and flotillin-2 leads to internalization and degradation of ErbB2. Furthermore, flotillin-1 and -2 were found to be in a molecular complex with ErbB2 and Hsp90. The depletion of one of these proteins results in disruption of this complex, followed by destabilization of ErbB2 at the membrane, and its internalization and degradation. As a consequence, ErbB2-triggered downstream signalling is inhibited. Our data demonstrate a novel mechanism for interfering with ErbB2 signalling, which potentially can have clinical impact.