title: Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses.
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.
authors.affiliation: Department of Surgery, Pathology and Cancer Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Naokazu
authors.initials: N
authors.lastname: Chiba
authors.forename: Valentine
authors.initials: V
authors.lastname: Comaills
authors.forename: Bunsyo
authors.initials: B
authors.lastname: Shiotani
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Takahashi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimada
authors.forename: Ken
authors.initials: K
authors.lastname: Tajima
authors.forename: Daniel
authors.initials: D
authors.lastname: Winokur
authors.forename: Tetsu
authors.initials: T
authors.lastname: Hayashida
authors.forename: Henning
authors.initials: H
authors.lastname: Willers
authors.forename: Elena
authors.initials: E
authors.lastname: Brachtel
authors.forename: Maria D M
authors.initials: MD
authors.lastname: Vivanco
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Lee
authors.initials: L
authors.lastname: Zou
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000528:radiation effects; D058750:Epithelial-Mesenchymal Transition / Q000528:radiation effects; D005260:Female; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011836:Radiation Tolerance / Q000528:radiation effects; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; C491257:HOXB9 protein, human; D006657:Histones; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases