Crockford, A;
Zalmas, LP;
Grönroos, E;
Dewhurst, SM;
McGranahan, N;
Cuomo, ME;
Encheva, V;
... Swanton, C; + view all
(2017)
Cyclin D mediates tolerance of genome-doubling in cancers with functional p53.
Annals of Oncology
, 28
(1)
pp. 149-156.
10.1093/annonc/mdw612.
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Abstract
BACKGROUND: Aneuploidy and chromosomal instability (CIN) are common features of human malignancy that fuel genetic heterogeneity. Although tolerance to tetraploidization, an intermediate state that further exacerbates CIN, is frequently mediated by TP53 dysfunction, we find that some genome-doubled tumours retain wild-type TP53. We sought to understand how tetraploid cells with a functional p53/p21-axis tolerate genome-doubling events. METHOD: We performed quantitative proteomics in a diploid/tetraploid pair within a system of multiple independently derived TP53 wild-type tetraploid clones arising spontaneously from a diploid progenitor. We characterized adapted and acute tetraploidization in a variety of flow cytometry and biochemical assays and tested our findings against human tumours through bioinformatics analysis of the TCGA dataset. RESULTS: Cyclin D1 was found to be specifically overexpressed in early but not late passage tetraploid clones, and this overexpression was sufficient to promote tolerance to spontaneous and pharmacologically induced tetraploidy. We provide evidence that this role extends to D-type cyclins and their overexpression confers specific proliferative advantage to tetraploid cells. We demonstrate that tetraploid clones exhibit elevated levels of functional p53 and p21 but override the p53/p21 checkpoint by elevated expression of cyclin D1, via a stoichiometry-dependent and CDK activity-independent mechanism. Tetraploid cells do not exhibit increased sensitivity to abemaciclib, suggesting that cyclin D-overexpressing tumours might not be specifically amenable to treatment with CDK4/6 inhibitors. CONCLUSION: Our study suggests that D-type cyclin overexpression is an acute event, permissive for rapid adaptation to a genome-doubled state in TP53 wild-type tumours and that its overexpression is dispensable in later stages of tumour progression.
| Type: | Article |
|---|---|
| Title: | Cyclin D mediates tolerance of genome-doubling in cancers with functional p53 |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/annonc/mdw612 |
| Publisher version: | https://doi.org/10.1093/annonc/mdw612 |
| Language: | English |
| Additional information: | Copyright © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Chromosomal instability, tetraploidy, p53, cyclin D, p21 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1545877 |
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