In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis

Abstract

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, 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 with inflammation and lymphocyte infiltration, but not blood cancers. These tumors are significantly larger and more penetrant, abundant, proliferative and metastatic than control tumors. In addition, they are highly aneuploid with tumor cells frequently being in early mitosis and showing mitotic abnormalities, including lagging and incorrectly segregating chromosomes. We further demonstrate in vitro that even though EMI1 overexpression may cause mitotic arrest and cell death, it also promotes chromosome instability (CIN) following delayed chromosome alignment and anaphase onset. In human solid tumors, EMI1 is co-expressed with many markers for CIN and EMI1 overexpression is a stronger marker for CIN than most well-established ones. The fact that Emi1 overexpression promotes CIN and the formation of solid cancers in vivo indicates that Emi1 overexpression actively drives solid tumorigenesis. These novel mechanistic insights have important clinical implications.

In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion

“…Data from 26 previously published breast cancer datasets were used to study the potential association between expression of each of the 44 collagen genes and distant metastasis-free survival, as described [23, 39]. Briefly, datasets were combined and statistical significance was determined according to a Cox proportional hazard model with 95% confidence interval (CI).…”

“…and the Nottingham Prognostic Index, were performed as described [17, 18]. Survival analyses were performed using a single clinical feature at a time, i.e., distant metastasis-free survival, recurrence-free survival, or overall survival, and by splitting the gene expression in tumors into below (low) and above (high) the median expression level, as described [19, 39]. Statistical analyses were performed using log-rank Mantel-Cox tests.…”

The F-Box Domain-Dependent Activity of EMI1 Regulates PARPi Sensitivity in Triple-Negative Breast Cancers

“…It has been shown that, compared to normal tissues, EMI1 expression is upregulated in human breast cancer (Hsu et al, 2002;Lehman et al, 2007;Shimizu et al, 2013;Vaidyanathan et al, 2016). However, some studies have reported a negative correlation between EMI1 protein levels and tumor grade in human breast cancer (Lehman et al, 2007;van de Vijver et al, 2002), in agreement with the fact that EMI1 is located in a genomic region (chromosome 6q25) frequently deleted in metastatic breast cancers (Cesari et al, 2003). Using a broadspectrum tumor tissue microarray (TMA) we confirmed that the majority of EMI1-positive samples were low-grade breast tumors, whereas samples from higher-grade tumors and lymph node metastasis expressed lower EMI1 levels ( Figure S7A).…”

Overexpression of Fbxo6 inactivates spindle checkpoint by interacting with Mad2 and BubR1

“…FBPs superfamily includes 70 members [14], several of which played critical roles in cell cycle control, such as Fbxw1 (Beta-TrcP) [15], Fbxw5 [16], Fbxw7 [17], Fbxl1 (Skp2) [18], Fbxl2 [19], Fbxo4 [20], Fbxo5 [21] and Fbxo31 [22]. However, the function of FBPs during mitosis remains unclear.…”