Mutation of Breast Cancer Cell Genomic DNA by APOBEC3B

Abstract

Abstract : Many breast cancers have somatic mutation spectra dominated by C-to-T transitions1-9. In the course of my training, funded by this grant, I discovered that the DNA cytosine deaminase APOBEC3B (A3B) likely generates a substantial portion of these mutations. A3B mRNA is upregulated in the majority of primary breast tumors and breast cancer cell lines. Endogenous A3B protein is predominantly nuclear and is the only detectable source of DNA C-to-U editing activity in breast cancer cell line extracts. Knockdown experiments show that endogenous A3B is responsible for elevated levels of genomic uracil, increased mutation frequencies, and Cto- T transitions. Furthermore, induced A3B over-expression causes cell cycle deviations, cell death, DNA fragmentation, gamma-H2AX accumulation, and C-to-T mutations. The preferred deamination signature of recombinant A3B explains a major proportion (20%) of the entire breast cancer base substitution mutation load. These data suggest a model in which A3Bcatalyzed deamination provides a chronic source of DNA damage in breast cancer that explains how some cancers evolve rapidly and manifest gross molecular and clinical heterogeneity.