Publications
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.
Type | Journal |
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ISBN | 2072-6694 (Print) 2072-6694 (Linking) |
Authors | Lee, C.; Fernandez, K. J.; Alexandrou, S.; Sergio, C. M.; Deng, N.; Rogers, S.; Burgess, A.; Caldon, C. E. |
Responsible Garvan Author | Associate Professor Liz Caldon |
Publisher Name | Cancers |
Published Date | 2020-08-01 |
Published Volume | 12 |
Published Issue | 8 |
Published Pages | 2268 |
Status | Always Electronic |
DOI | 10.3390/cancers12082268 |
URL link to publisher's version | https://www.ncbi.nlm.nih.gov/pubmed/32823571 |