Abstract:
:Homeobox 9 (HOXB9), a nontransforming transcription factor overexpressed in breast cancer, alters tumor cell fate and promotes tumor progression and metastasis. Here we show that HOXB9 confers resistance to ionizing radiation by promoting DNA damage response. In nonirradiated cells, HOXB9 induces spontaneous DNA damage, phosphorylated histone 2AX and p53 binding protein 1 foci, and increases baseline ataxia telangiectasia mutated (ATM) phosphorylation. Upon ionizing radiation, ATM is hyperactivated in HOXB9-expressing cells during the early stages of the double-stranded DNA break (DSB) response, accelerating accumulation of phosphorylated histone 2AX, mediator of DNA-damage checkpoint 1, and p53 binding protein 1, at DSBs and enhances DSB repair. The effect of HOXB9 on the response to ionizing radiation requires the baseline ATM activity before irradiation and epithelial-to-mesenchymal transition induced by TGF-β, a HOXB9 transcriptional target. Our results reveal the impact of a HOXB9-TGF-β-ATM axis on checkpoint activation and DNA repair, suggesting that TGF-β may be a key factor that links tumor microenvironment, tumor cell fate, DNA damage response, and radioresistance in a subset of HOXB9-overexpressing breast tumors.
journal_name
Proc Natl Acad Sci U S Aauthors
Chiba N,Comaills V,Shiotani B,Takahashi F,Shimada T,Tajima K,Winokur D,Hayashida T,Willers H,Brachtel E,Vivanco MD,Haber DA,Zou L,Maheswaran Sdoi
10.1073/pnas.1018867108subject
Has Abstractpub_date
2012-02-21 00:00:00pages
2760-5issue
8eissn
0027-8424issn
1091-6490pii
1018867108journal_volume
109pub_type
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