TY - JOUR
T1 - Activation of the ATM-Snail pathway promotes breast cancer metastasis
AU - Sun, Mianen
AU - Guo, Xiaojing
AU - Qian, Xiaolong
AU - Wang, Haibo
AU - Yang, Chunying
AU - Brinkman, Kathryn L.
AU - Serrano-Gonzalez, Monica
AU - Jope, Richard S.
AU - Zhou, Binhua
AU - Engler, David A.
AU - Zhan, Ming
AU - Wong, Stephen T.C.
AU - Fu, Li
AU - Xu, Bo
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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.
KW - ATM
KW - metastasis
KW - snail
UR - http://www.scopus.com/inward/record.url?scp=84867426083&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867426083&partnerID=8YFLogxK
U2 - 10.1093/jmcb/mjs048
DO - 10.1093/jmcb/mjs048
M3 - Article
C2 - 22923499
AN - SCOPUS:84867426083
SN - 1674-2788
VL - 4
SP - 304
EP - 315
JO - Journal of Molecular Cell Biology
JF - Journal of Molecular Cell Biology
IS - 5
ER -