APOBEC3B is an enzymatic source of mutation in breast cancer

Michael B. Burns, Lela Lackey, Michael A. Carpenter, Anurag Rathore, Allison M. Land, Brandon Leonard, Eric W. Refsland, Delshanee Kotandeniya, Natalia Tretyakova, Jason B. Nikas, Douglas Yee, Nuri A. Temiz, Duncan E. Donohue, Rebecca M. Mcdougle, William L. Brown, Emily K. Law, Reuben S. Harris

Research output: Contribution to journalArticlepeer-review

583 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)366-370
Number of pages5
JournalNature
Volume494
Issue number7437
DOIs
StatePublished - Feb 21 2013
Externally publishedYes

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'APOBEC3B is an enzymatic source of mutation in breast cancer'. Together they form a unique fingerprint.

Cite this