Abstract
BackgroundThe 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.ResultsHER2 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.ConclusionThese 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 materialThe online version of this article (doi:10.1186/s13059-016-1042-9) contains supplementary material, which is available to authorized users.
Highlights
The APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types
human epidermal receptor-2 (HER2) amplification, PTEN and NF1 somatic mutations are associated with the APOBEC3 signature It has recently been shown that HER2-enriched (HER2+) breast cancers are associated with a high burden of mutations attributable to APOBEC3B [9]
Mutations in PIK3CA were associated with the APOBEC3 signature, it has been suggested that APOBEC3 activity itself is the main driver of these helical domain mutations [23]
Summary
The APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types. Genomic instability is a well-recognized hallmark of cancer and is known to cause both aberrant chromosome architecture as well as mutational changes at the single nucleotide level [1]. We recently described the enrichment of APOBEC3 mutagenesis later in tumour evolution, occurring as subclonal mutations in estrogen receptor (ER)-negative breast cancer, lung adenocarcinoma, head and neck squamous carcinoma and bladder carcinoma, suggesting APOBEC3 may contribute to branched evolution in some tumour types [12,13,14]. Whether there is a mechanistic connection between the underlying causes of chromosomal copy number aberrations and the generation of APOBEC3 mutagenesis in HER2+ breast cancer has not been explored
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