Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer

Abstract

Genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but few drivers have been identified for this process. Due to their physiological roles in the genome reduplication of normal cells, we hypothesised that the oncogenes cyclins E1 and E2 may be drivers of genome doubling in cancer. We show that both cyclin E1 (CCNE1) and cyclin E2 (CCNE2) mRNA are significantly associated with high genome ploidy in breast cancers. By live cell imaging and flow cytometry, we show that cyclin E2 overexpression promotes aberrant mitosis without causing mitotic slippage, and it increases ploidy with negative feedback on the replication licensing protein, Cdt1. We demonstrate that cyclin E2 localises with core preRC (pre-replication complex) proteins (MCM2, MCM7) on the chromatin of cancer cells. Low CCNE2 is associated with improved overall survival in breast cancers, and we demonstrate that low cyclin E2 protects from excess genome rereplication. This occurs regardless of p53 status, consistent with the association of high cyclin E2 with genome doubling in both p53 null/mutant and p53 wildtype cancers. In contrast, while cyclin E1 can localise to the preRC, its downregulation does not prevent rereplication, and overexpression promotes polyploidy via mitotic slippage. Thus, in breast cancer, cyclin E2 has a strong association with genome doubling, and likely contributes to highly proliferative and genomically unstable breast cancers.

Methyl Ferulic Acid Attenuates Human Cardiac Fibroblasts Differentiation and Myocardial Fibrosis by Suppressing pRB-E2F1/CCNE2 and RhoA/ROCK2 Pathway

“…As a downstream transcriptional target, CCNE2 was also involved in cell cycle and cell proliferation. CCNE2 was a member of Cyclin E family and CCNE2 with the other Cyclin E family members functioned alike, which activated the CDK2 to promote cell cycle progression (Geng et al, 1996;Lee et al, 2020). In our results, we found that in TGF-β1-stimulated HCFs, the cell proliferation ability was enhanced and the cell cycle was promoted by improving percentages of the S and G2/M phase.…”

Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

“…Importantly, the effects of high levels of Cyclin E1 on chromosome instability seem to depend on CDK2 activity, as a hyperactive CDK2 knockin allele was sufficient to induce increased Cyclin E1-associated CDK2 activity and micronucleus formation in human colorectal cancer cells ( Hughes et al, 2013 ). CCNE1 and CCNE2 amplification, as well as increased mRNA expression, have been also correlated with whole genome doublings in human cancers ( Zack et al, 2013 ; Lee et al, 2020 ). One of the proposed mechanisms to explain how hyperactive Cyclin E/CDK2 causes genome doublings is the induction of mitotic failure or endoreduplication, with subsequent formation of polyploid cells.…”

Homologous recombination proficiency in ovarian and breast cancer patients

“…This can lead to genomic instability and drive the dysregulation of genes responsible for proliferation and cellular survival [22,27]. Cyclin E1 amplification occurs in 19.1% of all ovarian cancers [22,25] and 3.4% of breast cancers [28]. Most HRD cancer cells have direct deficiency in a gene or group of genes responsible for homologous recombination DNA repair, although upregulation of miRNAs can also cause HRD [21].…”