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Open AccessArticle

Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer

1
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
2
St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia
3
Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
4
Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
5
ANZAC Research Institute, Concord, NSW 2139, Australia
6
The University of Sydney Concord Clinical School, Faculty of Medicine and Health Concord, Sydney, NSW 2139, Australia
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(8), 2268; https://doi.org/10.3390/cancers12082268
Received: 5 July 2020 / Revised: 2 August 2020 / Accepted: 4 August 2020 / Published: 13 August 2020
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. View Full-Text
Keywords: cyclin E2; cyclin E1; genome doubling; genomic instability; p53 cyclin E2; cyclin E1; genome doubling; genomic instability; p53
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Lee, C.; Fernandez, K.J.; Alexandrou, S.; Sergio, C.M.; Deng, N.; Rogers, S.; Burgess, A.; Caldon, C.E. Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer. Cancers 2020, 12, 2268.

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