Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/8/2268 |
| _version_ | 1797558436073832448 |
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| author | Christine Lee Kristine J. Fernandez Sarah Alexandrou C. Marcelo Sergio Niantao Deng Samuel Rogers Andrew Burgess C. Elizabeth Caldon |
| author_facet | Christine Lee Kristine J. Fernandez Sarah Alexandrou C. Marcelo Sergio Niantao Deng Samuel Rogers Andrew Burgess C. Elizabeth Caldon |
| author_sort | Christine Lee |
| collection | DOAJ |
| description | 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 (<i>CCNE1</i>) and cyclin E2 (<i>CCNE2</i>) 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 <i>CCNE2</i> 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. |
| first_indexed | 2024-03-10T17:31:24Z |
| format | Article |
| id | doaj.art-301b0f41cd9a44d0ab7d33ee4f0ad7b5 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T17:31:24Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-301b0f41cd9a44d0ab7d33ee4f0ad7b52023-11-20T10:00:46ZengMDPI AGCancers2072-66942020-08-01128226810.3390/cancers12082268Cyclin E2 Promotes Whole Genome Doubling in Breast CancerChristine Lee0Kristine J. Fernandez1Sarah Alexandrou2C. Marcelo Sergio3Niantao Deng4Samuel Rogers5Andrew Burgess6C. Elizabeth Caldon7The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, AustraliaThe Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, AustraliaThe Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, AustraliaThe Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, AustraliaThe Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, AustraliaChildren’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, AustraliaANZAC Research Institute, Concord, NSW 2139, AustraliaThe Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, AustraliaGenome 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 (<i>CCNE1</i>) and cyclin E2 (<i>CCNE2</i>) 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 <i>CCNE2</i> 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.https://www.mdpi.com/2072-6694/12/8/2268cyclin E2cyclin E1genome doublinggenomic instabilityp53 |
| spellingShingle | Christine Lee Kristine J. Fernandez Sarah Alexandrou C. Marcelo Sergio Niantao Deng Samuel Rogers Andrew Burgess C. Elizabeth Caldon Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer Cancers cyclin E2 cyclin E1 genome doubling genomic instability p53 |
| title | Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer |
| title_full | Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer |
| title_fullStr | Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer |
| title_full_unstemmed | Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer |
| title_short | Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer |
| title_sort | cyclin e2 promotes whole genome doubling in breast cancer |
| topic | cyclin E2 cyclin E1 genome doubling genomic instability p53 |
| url | https://www.mdpi.com/2072-6694/12/8/2268 |
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