title: DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Paul O'Gorman Building, Huntley St., London, UK.
authors.forename: Nnennaya
authors.initials: N
authors.lastname: Kanu
authors.affiliation: UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Paul O'Gorman Building, Huntley St., London, UK.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Cerone
authors.affiliation: UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Paul O'Gorman Building, Huntley St., London, UK.
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
authors.forename: Lykourgos-Panagiotis
authors.initials: LP
authors.lastname: Zalmas
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Medical Biochemistry and Biophysics, Division of Translational Medicine and Chemical Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.affiliation: UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Paul O'Gorman Building, Huntley St., London, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Dietzen
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGranahan
authors.affiliation: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rogers
authors.affiliation: Howard Hughes Medical Institute, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Law
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Irina
authors.initials: I
authors.lastname: Gromova
authors.affiliation: Department of Mathematics and Technology, University of Applied Sciences Koblenz, RheinAhrCampus Remagen, Joseph-Rovan-Allee 2, D-53424, Remagen, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Kschischo
authors.affiliation: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Walton
authors.affiliation: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
authors.forename: Olivia W
authors.initials: OW
authors.lastname: Rossanese
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Medical Biochemistry and Biophysics, Division of Translational Medicine and Chemical Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.affiliation: Howard Hughes Medical Institute, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.affiliation: UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Paul O'Gorman Building, Huntley St., London, UK. subramanian.venkatesan@crick.ac.uk.|Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK. subramanian.venkatesan@crick.ac.uk.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Venkatesan
authors.affiliation: UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Paul O'Gorman Building, Huntley St., London, UK. charles.swanton@crick.ac.uk.|Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK. charles.swanton@crick.ac.uk.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D000071478:APOBEC Deaminases; D000970:Antineoplastic Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D004789:Enzyme Activation; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D005810:Multigene Family; D016296:Mutagenesis; D009154:Mutation; D009857:Oncogenes; D015398:Signal Transduction; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase
keywords: APOBEC; Genomic instability; Replication stress; Somatic mutation