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. Due to their roles in normal physiological endoreduplication of the genome for specialised cell types, we hypothesised that cyclin E1 and cyclin E2 may be drivers of genome doubling in cancer. We show that cyclin E2, but not cyclin E1, promotes genomic instability through increased re-replication to drive genome doubling. Using chromatin extracts we show that cyclin E2 localises and recruits core proteins (MCM2, MCM7) to the pre-replication complexes (preRC) necessary to initiate DNA replication, leading to increased whole genome replication. By contrast, cyclin E1 overexpression does not increase whole genome replication but instead leads to the depletion of Cdt1, the preRC factor required for DNA replication initiation. We recapitulate genome instability via genome doubling with the overexpression of cyclin E2, and karyotypes of these cyclin E2 overexpressing cells have acquired chromosomes and large chromosomal rearrangements during genomic instability. An examination of public datasets showed that cyclin E2 (but not cyclin E1) correlates with high ploidy and genomic instability across breast cancers. Thus cyclin E2 is a likely contributor to chromosomal instability in the evolution of breast cancer via its role in inappropriate whole genome duplication.
17 Mar 2019 - 20 Mar 2019