APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer
Manikandan Periyasamy,
Hetal Patel,
Chun-Fui Lai,
Van T.M. Nguyen,
Ekaterina Nevedomskaya,
Alison Harrod,
Roslin Russell,
Judit Remenyi,
Anna Maria Ochocka,
Ross S. Thomas,
Frances Fuller-Pace,
Balázs Győrffy,
Carlos Caldas,
Naveenan Navaratnam,
Jason S. Carroll,
Wilbert Zwart,
R. Charles Coombes,
Luca Magnani,
Laki Buluwela,
Simak Ali
Affiliations
Manikandan Periyasamy
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Hetal Patel
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Chun-Fui Lai
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Van T.M. Nguyen
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Ekaterina Nevedomskaya
Department of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
Alison Harrod
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Roslin Russell
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Judit Remenyi
Division of Cancer Research, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Anna Maria Ochocka
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Ross S. Thomas
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Frances Fuller-Pace
Division of Cancer Research, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Balázs Győrffy
MTA TTK Lendület Cancer Biomarker Research Group, Second Department of Pediatrics, Semmelweis University and MTA-SE Pediatrics and Nephrology Research Group, Budapest 1085, Hungary
Carlos Caldas
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Naveenan Navaratnam
MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Jason S. Carroll
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Wilbert Zwart
Department of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
R. Charles Coombes
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Luca Magnani
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Laki Buluwela
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
Simak Ali
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
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.
