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 doublestranded 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.
| Original language | English |
|---|---|
| Pages (from-to) | 2760-2765 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 109 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2012 Feb 21 |
| Externally published | Yes |
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Cite this
Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses. / Chiba, Naokazu; Comaills, Valentine; Shiotani, Bunsyo; Takahashi, Fumiyuki; Shimada, Toshiyuki; Tajima, Ken; Winokur, Daniel; Hayashida, Tetsu; Willers, Henning; Brachtel, Elena; Vivanco, Maria D M; Haber, Daniel A.; Zou, Lee; Maheswaran, Shyamala.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 8, 21.02.2012, p. 2760-2765.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses
AU - Chiba, Naokazu
AU - Comaills, Valentine
AU - Shiotani, Bunsyo
AU - Takahashi, Fumiyuki
AU - Shimada, Toshiyuki
AU - Tajima, Ken
AU - Winokur, Daniel
AU - Hayashida, Tetsu
AU - Willers, Henning
AU - Brachtel, Elena
AU - Vivanco, Maria D M
AU - Haber, Daniel A.
AU - Zou, Lee
AU - Maheswaran, Shyamala
PY - 2012/2/21
Y1 - 2012/2/21
N2 - 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 doublestranded 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.
AB - 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 doublestranded 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.
UR - http://www.scopus.com/inward/record.url?scp=84857415007&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84857415007&partnerID=8YFLogxK
U2 - 10.1073/pnas.1018867108
DO - 10.1073/pnas.1018867108
M3 - Article
C2 - 21930940
AN - SCOPUS:84857415007
VL - 109
SP - 2760
EP - 2765
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 8
ER -