Activation of the ATM-Snail pathway promotes breast cancer metastasis

Mianen Sun, Xiaojing Guo, Xiaolong Qian, Haibo Wang, Chunying Yang, Kathryn L. Brinkman, Monica Serrano-Gonzalez, Richard S Jope, Binhua Zhou, David A. Engler, Ming Zhan, Stephen T C Wong, Li Fu, Bo Xu

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)304-315
Number of pages12
JournalJournal of Molecular Cell Biology
Volume4
Issue number5
DOIs
StatePublished - Oct 1 2012
Externally publishedYes

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Keywords

  • ATM
  • metastasis
  • snail

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Genetics

Cite this

Sun, M., Guo, X., Qian, X., Wang, H., Yang, C., Brinkman, K. L., Serrano-Gonzalez, M., Jope, R. S., Zhou, B., Engler, D. A., Zhan, M., Wong, S. T. C., Fu, L., & Xu, B. (2012). Activation of the ATM-Snail pathway promotes breast cancer metastasis. Journal of Molecular Cell Biology, 4(5), 304-315. https://doi.org/10.1093/jmcb/mjs048