APOBEC3B drives breast cancer evolution via an early selection bottleneck
Endogenous processes of mutation and selection shape cancer evolution, yet how they influence tumour trajectories remains unclear. APOBEC3 cytidine deaminases are endogenous drivers of mutagenesis in many cancers. Here we show, by inferring evolutionary trajectories of primary human breast cancers and by experimentally modelling breast cancer evolution in mice, that APOBEC3B (A3B) imposes an early selection bottleneck in tumour development that is independent of cytidine deamination. In mice, A3B expression delays tumour initiation by imposing an early DNA damage–induced bottleneck associated with genomic instability, compromised cell viability, and extended copy number evolution. Tumours overcome this bottleneck by selecting adaptive alterations that activate DNA-repair and stress-response pathways, enabling malignant progression. Consistently, in human breast cancers, high A3B expression correlates with prolonged evolutionary trajectories, increased copy number gains, and basal-like transcriptional states with poor clinical features. Together, these findings identify A3B as a dual mediator of selection and mutagenesis that orchestrates tumour evolution, delaying initiation yet promoting aggressive disease.