Activation of the ATM-Snail pathway promotes breast cancer metastasis
Activation of the ATM-Snail pathway promotes breast cancer metastasis
复制标题
ATM-Snail 通路的激活促进乳腺癌转移。
DOI：
10.1093/jmcb/mjs048
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发表时间：
2012-10-01
影响因子：
5.5
通讯作者：
Xu, Bo
中科院分区：
文献类型：
--
作者：
Sun, Mianen;Guo, Xiaojing;Xu, Bo
DNA 损伤反应 (DDR) 对于维持遗传稳定性至关重要，并在早期肿瘤发生过程中充当抗癌屏障。然而，DDR 在肿瘤进展和转移中的作用却鲜为人知。在这里，我们证明了 ATM 激酶（关键的 DDR 元件之一）在伴有淋巴结转移的晚期乳腺肿瘤组织中高度活跃，并且这种过度活跃与上皮间质转化标记物 Snail 的表达升高相关。在分子水平上，我们证明 ATM 通过 Serine-100 磷酸化来调节 Snail 的稳定性。通过质谱分析，我们确定 HSP90 是 Snail 响应 DNA 损伤的关键结合蛋白。 HSP90 结合并稳定磷酸化的 Snail。我们进一步提供了体外和体内证据，证明 ATM 介导的 Snail 磷酸化的激活可促进肿瘤侵袭和转移。最后，我们证明 Snail Serine-100 磷酸化在有淋巴结转移的乳腺癌组织中升高，表明 ATM-Snail 通路的临床意义。总之，我们的研究结果提供了强有力的证据，证明 ATM-Snail 通路促进肿瘤转移，强调了 DDR 在肿瘤侵袭和转移中先前未描述的作用。
The DNA damage response (DDR) is critical for the maintenance of genetic stability and serves as an anti-cancer barrier during early tumorigenesis. However, the role of the DDR in tumor progression and metastasis is less known. Here, we demonstrate that the ATM kinase, one of the critical DDR elements, is hyperactive in late stage breast tumor tissues with lymph-node metastasis and this hyperactivity correlates with elevated expression of the epithelial-mesenchymal transition marker, Snail. At the molecular level, we demonstrate that ATM regulates Snail stabilization by phosphorylation on Serine-100. Using mass spectrometry, we identified HSP90 as a critical binding protein of Snail in response to DNA damage. HSP90 binds to and stabilizes phosphorylated Snail. We further provide in vitro and in vivo evidence that activation of ATM-mediated Snail phosphorylation promotes tumor invasion and metastasis. Finally, we demonstrate that Snail Serine-100 phosphorylation is elevated in breast cancer tissues with lymph-node metastasis, indicating clinical significance of the ATM-Snail pathway. Together, our findings provide strong evidence that the ATM-Snail pathway promotes tumor metastasis, highlighting a previously undescribed role of the DDR in tumor invasion and metastasis.