DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer.
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<h4>Background</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.
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Cell Transformation, Neoplastic
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Ataxia Telangiectasia Mutated Proteins
Signal Transduction & Molecular Pharmacology
Target Evaluation and Molecular Therapeutics
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Genome biology, 2016, 17 (1), pp. 185 - ?