Activation of the ATM-Snail pathway promotes breast cancer metastasis.
J Mol Cell Biol
; 4(5): 304-15, 2012 Oct.
Article
em En
| MEDLINE
| ID: mdl-22923499
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Neoplasias da Mama
/
Transdução de Sinais
/
Proteínas Serina-Treonina Quinases
/
Proteínas de Ciclo Celular
/
Proteínas Supressoras de Tumor
/
Proteínas de Ligação a DNA
/
Metástase Linfática
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Mol Cell Biol
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos