Abstract A133: The DNA cytosine deaminase APOBEC3B drives mutagenesis in breast cancer

Abstract

Abstract A typical breast cancer accumulates hundreds to thousands of somatic mutations. Breast cancer mutation spectra are often dominated by C-to-T transition mutations, which occur in a mostly dispersed manner but can also occur in localized clusters called kataegis. Several lines of evidence indicate that the innate immune DNA cytosine deaminase APOBEC3B is the primary cause of these mutations. First, APOBEC3B mRNA is up-regulated in the majority of primary breast tumors and breast cancer cell lines. Second, endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell line extracts. Third, APOBEC3B knockdown causes a corresponding decrease in genomic uracil concentrations, mutation frequencies, and C-to-T mutation levels in breast cancer cell lines. Fourth, the biochemical signature of APOBEC3B is over-represented in breast cancer mutation spectra. Fifth, breast carcinomas that express high levels of APOBEC3B have twice as many mutations as those expressing low levels. Finally, high levels of APOBEC3B associate with more aggressive disease including shorter durations of survival. All of these data are consistent with a model in which APOBEC3B-catalyzed DNA cytosine deamination provides a chronic source of DNA damage and mutagenesis in breast carcinomas that may help to explain how some tumors evolve rapidly and manifest gross heterogeneity. Citation Format: Reuben Harris. The DNA cytosine deaminase APOBEC3B drives mutagenesis in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A133.