Abstract 3586: Overexpression of Emi1 causes chromosomal instability and cancer

Abstract

Chromosomal Instability (CIN) is a common occurrence in solid cancer associated with poor survival in patients. A significant percentage of these tumors show abnormal chromosomes with near-triploid or tetraploid numbers exhibiting numerical CIN (nCIN). nCIN is caused mainly due to deregulation of cell cycle proteins. Early Mitotic Inhibitor 1 (Emi1) is a cell cycle protein that regulates the activity of E3 ubiquitin ligase, Anaphase Promoting Complex/Cyclosome (APC/C), which targets many cell cycle proteins for degradation. Emi1 is overexpressed in many solid tumors but not blood cancers. Unpublished data from our lab has shown that Emi1 overexpression in mouse models causes more penetrant and metastatic tumor than control tumors. Breast cancer tissues show significantly high expression of Emi1 at protein level as compared to control breast tissue samples, in agreement with the microarray data from The Cancer Genome Atlas (TCGA). In addition, Emi1 expression from breast cancer TCGA data strongly correlated with the chromosomal instability signature than many of the well-established genes known to promote CIN phenotype. To understand the mechanisms of CIN due to Emi1 overexpression, we overexpressed Emi1 in HeLa cells expressing GFP-tagged histone protein to monitor the cells during mitosis by live cell imaging. HeLa cells overexpressing Emi1 show CIN following delays in both chromosome alignment at the metaphase plate and, subsequently, anaphase onset (p = 0.0008 and p = 0.0028). There is a significant increase in CIN phenotypes and abnormal mitoses such as anaphase bridges/lagging chromosomes, mitotic arrest and cell death. These results indicate that Emi1 overexpression actively drives tumorigenesis. Citation Format: Srividya Vaidyanathan, Kathleen Cato, Sandra Pavey, Nikolas K. Haass, Brian G. Gabrielli, Pascal HG Duijf. Overexpression of Emi1 causes chromosomal instability and cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3586.