title: Activation of the ATM-Snail pathway promotes breast cancer metastasis.
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.
authors.affiliation: Department of Radiation Oncology, The Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Mianen
authors.initials: M
authors.lastname: Sun
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Guo
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Qian
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.forename: Chunying
authors.initials: C
authors.lastname: Yang
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Brinkman
authors.forename: Monica
authors.initials: M
authors.lastname: Serrano-Gonzalez
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
authors.forename: Binhua
authors.initials: B
authors.lastname: Zhou
authors.forename: David A
authors.initials: DA
authors.lastname: Engler
authors.forename: Ming
authors.initials: M
authors.lastname: Zhan
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases