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.
Highlights
Genome doubling occurs in ~30–37% of primary cancers [1,2], and up to 56% of metastatic cancers [3]
We first determined how cyclin E1 and cyclin E2 related to genome ploidy by examining the relationship between the expression of the cyclins E1 and E2 genes, CCNE1 and CCNE2, and the genome doubling status of TCGA breast cancers (n = 831)
Cyclin E1 drives polyploidy in high-grade serous ovarian cancer in association with CCNE1 gene amplification [7] and is generally associated with genome doubling [1], but cyclin E2 has not been reported in this context
Summary
Genome doubling occurs in ~30–37% of primary cancers [1,2], and up to 56% of metastatic cancers [3]. A doubled genome provides an advantage to cancer cells by increasing tolerance to chromosomal instability [4], and increasing aneuploidy, cancer cell heterogeneity and intrinsic resistance to therapy [5,6]. Whole genome doubling leads to cancers with two-fold higher driver amplification events [3] and is significantly associated with poorer overall survival [1]. Cancer subtypes differ in their associated genomic drivers of whole genome doubling, but the drivers for each cancer subtype are poorly characterised [1]. A known driver is cyclin E1 [1,2], which is associated with polyploidy in high-grade serous ovarian cancer [7].
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