PO-184 Role of ubiquitin-conjugating enzymes in chromosome instability and breast cancer metastasis

• Published in: ESMO open Vol. 3; no. Suppl 2; p. A93
• Main Authors: Salvador, F, Cejalvo, JM, Guiu, M, Fernández, E, Paré, L, Prat, A, Gomis, RR
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-07-2018
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1136/esmoopen-2018-EACR25.223

IntroductionChromosome Instability (CIN) is a hallmark in cancer being aneuploidy found in most of the tumours. In addition, high levels of CIN in primary tumours predict poor outcome in several cancer types. During last years, it has been demonstrated the role of aneuploidy during primary tumour generation in some transgenic mouse models. However, the role and functional consequences of CIN and aneuploidy during the metastatic process has not been deeply explored.Material and methodsPrevious screening from the group (Gawrzak et al. 2018) identified several candidates genes potentially relevant in breast cancer (BC) dormancy.WB and IF were performed for analysis of mitosis and study of chromosome segregation.Cells were labelled with GFP-Luciferease for tracking tumour cells in mice.CIN70 signature was obtained by analysing RNA expression data from paired primary and metastatic tissues from BC (Cejalvo et al. 2017).Results and discussionsTaking advantage from a previous loss of function screening approach in dormant breast cancer cells we have identified an Ubiquitin-conjugating enzyme (UBE) as a candidate gene to control metastasis in BC. UBE has a pivotal role during cell division by controlling the stability of key mitotic players. UBE abrogation prolongs the spindle assembly checkpoint in several breast cancer cell lines, thus delaying mitosis exit. Further analysis shows that UBE depletion impaired the normal segregation of chromosomes during cell division increasing aneuploidy rates. Interestingly, in vivo studies with different breast cancer cell lines show an increase in the metastatic abilities of UBE downregulated cells. Additionally, we compared a signature of chromosomal instability (CIN70) between paired primary and metastatic tissues form BC. CIN70 score is clearly increased in metastasis, emphasising the importance of aneuploidy for the acquisition of the traits required for cancer metastasis in BC.ConclusionOverall, our results suggest that CIN generated by disturbed levels of UBE increases cell plasticity to facilitate metastatic growth in BC.