Uncontrolled genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but relatively few drivers have been identified for this process. Cyclin E1 and cyclin E2 are cell cycle regulators whose dysregulation in oncogenesis promotes both increased proliferation and genomic instability. Here we show that cyclin E2, but not cyclin E1, promotes genomic instability through increased DNA re-replication to drive genome doubling. Cyclin E2 localises and recruits core proteins to the pre-replication complexes (preRC) on chromatin, leading to increased genome re-replication. An examination of large datasets shows that cyclin E2 correlates with genome doubling and genomic instability across breast cancers. Finally, we recapitulate genome instability via genome doubling with the overexpression of cyclin E2, demonstrating a potential therapeutic axis via inhibition of the cyclin E2 activated kinase, CDK2.