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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463708/ https://www.ncbi.nlm.nih.gov/pubmed/32823571 http://dx.doi.org/10.3390/cancers12082268 |
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author | Lee, Christine Fernandez, Kristine J. Alexandrou, Sarah Sergio, C. Marcelo Deng, Niantao Rogers, Samuel Burgess, Andrew Caldon, C. Elizabeth |
author_facet | Lee, Christine Fernandez, Kristine J. Alexandrou, Sarah Sergio, C. Marcelo Deng, Niantao Rogers, Samuel Burgess, Andrew Caldon, C. Elizabeth |
author_sort | Lee, Christine |
collection | PubMed |
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 (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. |
format | Online Article Text |
id | pubmed-7463708 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74637082020-09-02 Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer Lee, Christine Fernandez, Kristine J. Alexandrou, Sarah Sergio, C. Marcelo Deng, Niantao Rogers, Samuel Burgess, Andrew Caldon, C. Elizabeth Cancers (Basel) Article 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. MDPI 2020-08-13 /pmc/articles/PMC7463708/ /pubmed/32823571 http://dx.doi.org/10.3390/cancers12082268 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lee, Christine Fernandez, Kristine J. Alexandrou, Sarah Sergio, C. Marcelo Deng, Niantao Rogers, Samuel Burgess, Andrew Caldon, C. Elizabeth Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463708/ https://www.ncbi.nlm.nih.gov/pubmed/32823571 http://dx.doi.org/10.3390/cancers12082268 |
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