APOBEC3B is upregulated and accounts for a large proportion of mutations in breast cancer.

  • Major finding: APOBEC3B is upregulated and accounts for a large proportion of mutations in breast cancer.

  • Concept: High APOBEC3B levels are associated with increased overall mutation load and TP53 inactivation.

  • Impact: APOBEC3B-induced mutations may promote tumor development, heterogeneity, and drug resistance.

Cytosine-to-thymine (C-to-T) transitions dominate the mutation spectra of many cancers, including melanoma and breast cancer. These point mutations can occur spontaneously, as in the liver; via error-prone lesion bypass synthesis, as in melanoma; or via the enzymatic activity of a family of cytosine deaminases, which consists of activation-induced deaminase and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins. Burns and colleagues detected upregulation of APOBEC3B but not of any other family members in 28 of 38 breast cancer cell lines as well as in primary human breast cancer samples compared with matched normal tissue, suggesting that this enzyme may specifically mediate C-to-T mutations in this tumor type. Consistent with this idea, APOBEC3B protein localized to the nucleus and was necessary and sufficient to induce deaminase activity in breast cancer cells. Depletion of endogenous APOBEC3B resulted in decreased genomic uracil levels and reduced mutation frequencies, whereas high APOBEC3B expression in breast cancer cells was correlated with accumulation of C-to-T transitions within susceptible genes, including TP53 and MYC. Similarly, human breast tumors with elevated APOBEC3B expression exhibited a 2-fold increase in both C-to-T and overall mutation loads and were positively associated with TP53 inactivation. Moreover, overexpression of wild-type but not catalytically inactive APOBEC3B enhanced DNA fragmentation and formation of phosphorylated histone H2AX foci, delayed cell-cycle arrest, and induced cell death, suggesting that APOBEC3B-mediated deamination promotes chronic DNA damage and genomic instability that may facilitate tumor development and select for TP53 loss. Although additional work is needed to define APOBEC3B regulation, these results identify APOBEC3B as a principal driver of mutations in breast cancer and suggest that inhibition of this enzyme may limit tumor progression and the acquisition of drug resistance mutations.

Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM, Leonard B, et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 2013 Feb 6 [Epub ahead of print].

©2013 American Association for Cancer Research.
2013