title: APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer.
abstract: Estrogen receptor α (ERα) is the key transcriptional driver in a large proportion of breast cancers. We report that APOBEC3B (A3B) is required for regulation of gene expression by ER and acts by causing C-to-U deamination at ER binding regions. We show that these C-to-U changes lead to the generation of DNA strand breaks through activation of base excision repair (BER) and to repair by non-homologous end-joining (NHEJ) pathways. We provide evidence that transient cytidine deamination by A3B aids chromatin modification and remodelling at the regulatory regions of ER target genes that promotes their expression. A3B expression is associated with poor patient survival in ER+ breast cancer, reinforcing the physiological significance of A3B for ER action.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Periyasamy
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Hetal
authors.initials: H
authors.lastname: Patel
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Chun-Fui
authors.initials: CF
authors.lastname: Lai
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Van T M
authors.initials: VTM
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Nevedomskaya
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Harrod
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.affiliation: Division of Cancer Research, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Judit
authors.initials: J
authors.lastname: Remenyi
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Ochocka
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Ross S
authors.initials: RS
authors.lastname: Thomas
authors.affiliation: Division of Cancer Research, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Fuller-Pace
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Second Department of Pediatrics, Semmelweis University and MTA-SE Pediatrics and Nephrology Research Group, Budapest 1085, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Naveenan
authors.initials: N
authors.lastname: Navaratnam
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
authors.affiliation: Department of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Magnani
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Laki
authors.initials: L
authors.lastname: Buluwela
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. Electronic address: simak.ali@imperial.ac.uk.
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003562:Cytidine / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D059766:DNA End-Joining Repair; D003641:Deamination; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015778:Minor Histocompatibility Antigens; D011379:Prognosis; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014158:Transcription, Genetic; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D003562:Cytidine; D004247:DNA; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase