Oral Presentation 28th Lorne Cancer Conference 2016

In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis (#23)

Srividya Vaidyanathan 1 2 , Kathleen Cato 1 2 , Lu Tang 1 3 , Sandra Pavey 1 , Nikolas K Haass 1 , Brian G Gabrielli 1 , Pascal HG Duijf 1
  1. University of Queensland Diamantina Institute, Brisbane, QLD, Australia
  2. Equal contribution,
  3. School of Basic Medical Sciences, Fudan University, Shanghai, China

Cell cycle genes are often aberrantly expressed in cancer, but how their misexpression drives tumorigenesis mostly remains unclear. From S phase to early mitosis, EMI1 (also known as FBXO5) inhibits the anaphase-promoting complex/cyclosome (APC/C), which controls cell cycle progression through the sequential degradation of various substrates. By analyzing 7403 human tumor samples, we find that EMI1 overexpression is widespread in solid tumors but not in blood cancers. In solid cancers, EMI1 overexpression is a strong prognostic marker for poor patient outcome. To investigate causality, we generated a transgenic mouse model in which we overexpressed Emi1. Emi1-overexpressing animals develop a wide variety of solid tumors, in particular adenomas and carcinomas. These tumors are significantly larger and more penetrant, abundant and metastatic than control tumors. In addition, they are highly aneuploid with 75% of mitoses showing abnormal spindles, lagging chromosomes and/or misaligned chromosomes. In human solid tumors, EMI1 is co-expressed with many markers for chromosome instability and EMI1 overexpression is a stronger marker for chromosome instability than most well established ones. The fact that Emi1 overexpression promotes chromosome instability and the formation of solid cancers in vivo indicates that Emi1 overexpression actively drives solid tumorigenesis. These novel insights have important clinical implications.

  1. In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis. Srividya Vaidyanathan*, Kathleen Cato*, Lu Tang, Sandra Pavey, Nikolas K Haass, Brian G Gabrielli, Pascal HG Duijf#. Submitted. *Equal contribution.