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.