title: APOBEC3B is an enzymatic source of mutation in breast cancer.
abstract: Several mutations are required for cancer development, and genome sequencing has revealed that many cancers, including breast cancer, have somatic mutation spectra dominated by C-to-T transitions. Most of these mutations occur at hydrolytically disfavoured non-methylated cytosines throughout the genome, and are sometimes clustered. Here we show that the DNA cytosine deaminase APOBEC3B is a probable source of these mutations. APOBEC3B messenger RNA is upregulated in most primary breast tumours and breast cancer cell lines. Tumours that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53. Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell-line extracts. Knockdown experiments show that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression causes cell cycle deviations, cell death, DNA fragmentation, γ-H2AX accumulation and C-to-T mutations. Our data suggest a model in which APOBEC3B-catalysed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumours evolve rapidly and manifest heterogeneity.
authors: Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors: Michael B
authors: MB
authors: Burns
authors: Lela
authors: L
authors: Lackey
authors: Michael A
authors: MA
authors: Carpenter
authors: Anurag
authors: A
authors: Rathore
authors: Allison M
authors: AM
authors: Land
authors: Brandon
authors: B
authors: Leonard
authors: Eric W
authors: EW
authors: Refsland
authors: Delshanee
authors: D
authors: Kotandeniya
authors: Natalia
authors: N
authors: Tretyakova
authors: Jason B
authors: JB
authors: Nikas
authors: Douglas
authors: D
authors: Yee
authors: Nuri A
authors: NA
authors: Temiz
authors: Duncan E
authors: DE
authors: Donohue
authors: Rebecca M
authors: RM
authors: McDougle
authors: William L
authors: WL
authors: Brown
authors: Emily K
authors: EK
authors: Law
authors: Reuben S
authors: RS
authors: Harris
mesh_terms: D001483:Base Sequence; D055162:Biocatalysis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D016923:Cell Death; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D003641:Deamination; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D015778:Minor Histocompatibility Antigens; D016296:Mutagenesis / Q000235:genetics; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014498:Uracil / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; C468783:H2AX protein, human; D006657:Histones; D015778:Minor Histocompatibility Antigens; D016159:Tumor Suppressor Protein p53; D014498:Uracil; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase
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