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Published on: December 19, 2019

Activation of the ATM-Snail pathway promotes breast cancer metastasis

Mianen Sun1, Xiaojing Guo, Xiaolong Qian

  • 1Department of Radiation Oncology, The Methodist Hospital Research Institute, Houston, TX 77030, USA.

Journal of Molecular Cell Biology
|August 28, 2012
PubMed

Insights

The DNA damage response (DDR) pathway, specifically ATM kinase, promotes breast cancer metastasis by stabilizing Snail. This ATM-Snail pathway is active in metastatic tumors, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • The DNA damage response (DDR) maintains genetic stability and acts as an early anti-cancer mechanism.
  • The role of DDR in advanced tumor progression and metastasis remains largely unexplored.

Purpose of the Study:

  • To investigate the role of ATM kinase, a key DDR component, in breast cancer metastasis.
  • To elucidate the molecular mechanisms linking DDR to epithelial-mesenchymal transition (EMT) and metastasis.

Main Methods:

  • Analysis of ATM kinase activity and Snail expression in late-stage breast tumors with lymph-node metastasis.
  • In vitro and in vivo experiments to determine ATM's regulation of Snail.
  • Mass spectrometry to identify Snail-binding proteins involved in DNA damage response.

Main Results:

  • ATM kinase is hyperactive in metastatic breast tumors, correlating with elevated Snail expression.
  • ATM phosphorylates Snail at Serine-100, leading to its stabilization.
  • HSP90 binds to phosphorylated Snail, further enhancing its stability.
  • ATM-mediated Snail phosphorylation promotes tumor invasion and metastasis in vitro and in vivo.
  • Elevated Snail Serine-100 phosphorylation is observed in human breast cancer tissues with lymph-node metastasis.

Conclusions:

  • The ATM-Snail signaling pathway plays a significant role in promoting breast cancer invasion and metastasis.
  • This pathway represents a novel target for anti-metastatic therapies in breast cancer.
  • Highlights a previously unrecognized function of the DDR in driving tumor metastasis.

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