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Background  The APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types. Although many studies have documented the downstream effects of APOBEC3 activity through next-generation sequencing, less is known about their upstream regulation. In this study, we sought to identify a molecular basis for APOBEC3 expression and activation.    Results   HER2  amplification and  PTEN  loss promote DNA replication stress and APOBEC3B activity  in vitro  and correlate with APOBEC3 mutagenesis  in vivo . HER2-enriched breast carcinomas display evidence of elevated levels of replication stress-associated DNA damage  in vivo . Chemical and cytotoxic induction of replication stress, through aphidicolin, gemcitabine, camptothecin or hydroxyurea exposure, activates transcription of  APOBEC3B  via an ATR/Chk1-dependent pathway  in vitro . APOBEC3B activation can be attenuated through repression of oncogenic signalling, small molecule inhibition of receptor tyrosine kinase signalling and alleviation of replication stress through nucleoside supplementation.    Conclusion  These data link oncogene, loss of tumour suppressor gene and drug-induced replication stress with APOBEC3B activity, providing new insights into how cytidine deaminase-induced mutagenesis might be activated in tumourigenesis and limited therapeutically.    Electronic supplementary material  The online version of this article (doi:10.1186/s13059-016-1042-9) contains supplementary material, which is available to authorized users.

DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer