title: B-Myb Induces APOBEC3B Expression Leading to Somatic Mutation in Multiple Cancers.
abstract: The key signature of cancer genomes is the accumulation of DNA mutations, the most abundant of which is the cytosine-to-thymine (C-to-T) transition that results from cytosine deamination. Analysis of The Cancer Genome Atlas (TCGA) database has demonstrated that this transition is caused mainly by upregulation of the cytosine deaminase APOBEC3B (A3B), but the mechanism has not been completely characterized. We found that B-Myb (encoded by MYBL2) binds the A3B promoter, causing transactivation, and this is responsible for the C-to-T transitions and DNA hypermutation in breast cancer cells. Analysis of TCGA database yielded similar results, supporting that MYBL2 and A3B are upregulated and putatively promote C-to-T transitions in multiple cancer types. Moreover, blockade of EGF receptor with afatinib attenuated B-Myb-A3B signaling, suggesting a clinically relevant means of suppressing mutagenesis. Our results suggest that B-Myb-A3B contributes to DNA damage and could be targeted by inhibiting EGF receptor.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Ni
authors.initials: CN
authors.lastname: Hsiung
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ling-Yueh
authors.initials: LY
authors.lastname: Hu
authors.affiliation: Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
authors.affiliation: Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Huan-Ming
authors.initials: HM
authors.lastname: Hsu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Taiwan Biobank, Academia Sinica, Taipei, Taiwan.|College of Public Health, China Medical University, Taichung, Taiwan.
authors.forename: Chen-Yang
authors.initials: CY
authors.lastname: Shen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D015778:Minor Histocompatibility Antigens / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C064352:MYBL2 protein, human; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D015534:Trans-Activators; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase