APOBEC3B is an enzymatic source of mutation in breast cancer

Abstract

The DNA cytosine deaminase APOBEC3B is shown to be overexpressed and highly active in most breast cancers; deamination by APOBEC3B could serve as an endogenous, continual source of DNA damage leading to mutations, including C-to-T transitions and other aberrations seen in many breast tumours. The profile of C-to-T transition mutations in breast cancer suggests a non-spontaneous origin. This paper shows that some of these mutations may arise from the upregulation of a cytosine deaminase, APOBEC3B (A3B), in such cancer cells. Deamination catalysed by A3B could serve as an endogenous, continual source of DNA damage that leads to mutations and DNA fragmentation, whereas inactivation of TP53, which is frequently observed in cells overexpressing A3B, would prevent the elimination of such damaged cells by apoptosis. A3B may be a useful marker for breast cancer and also a candidate for targeted intervention, especially given its non-essential nature. 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 transitions1,2,3,4,5,6,7,8,9. Most of these mutations occur at hydrolytically disfavoured10 non-methylated cytosines throughout the genome, and are sometimes clustered8. 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.