APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer

• APOBEC3B is associated with poor survival in ER+ breast cancer patients
• APOBEC3B controls breast cancer cell growth by promoting ER transcriptional activity
• APOBEC3B can cause C-to-U mutations at ER target genes, to activate DNA repair
• Repair of APOBEC3B-induced lesions allows chromatin remodelling that stimulates gene expression

SummaryEstrogen 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.

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