Abstract B24: Loss of expression of the endogenous ETS factor ESE3/EHF is associated with a distinct tumor subtype with stem-like and basal cell features
Authors: Mello-Grand Maurizia , Sarti Manuela , D'Ambrosio Gioacchino , Sessa Fausto , Thalmann George , Chiorino Giovanna , Catapano Carlo V. , Carbone Giuseppina MR , Albino Domenico , Singh Vijay Kumar , Civenni Gianluca , Longoni Nicole , Ghimenti Chiara , Ostano Paola , Pinton Sandra 
Published: May 2013

Abstract
Gene fusions leading to ectopic expression of ETS transcription factors are frequent in prostate tumors. However, the impact of endogenously expressed ETS factors on prostate tumorigenesis has not been deeply investigated. A comprehensive analysis of the ETS transcriptional network in normal and prostate tumor samples revealed frequent deregulation of multiple ETS factors, including endogenously expressed ETS like ESE3/EHF. We found that ETS gene expression patterns could be used to classify prostate tumors in subgroups characterized by partially distinct transcriptional and biological features. To further explore this concept we analyzed in greater details the properties of the group of ETS fusion negative tumors characterized by exclusive loss of ESE3/EHF expression without other ETS gene alterations (ESE3low tumors). ESE3low tumors represented approximately 25% of all tumors in multiple patient cohorts. Loss of ESE3/EHF expression determined by IHC on tissue microarray (TMAs) was an early event occurring at the level of HGPINs and tumors. Furthermore, reduced or absent ESE3/EHF stain in TMAs was associated with significantly increased biochemical relapse and reduced 10-year survival following prostatectomy for primary prostate cancer, independently of ERG status. Consistent with a role in tumor initiation and progression, ESE3/EHF knockdown in immortalized prostate epithelial cells induced epithelial-to-mesenchymal transition (EMT), in vitro stem-like properties and in vivo tumour-initiating and metastatic capability. Conversely, re-expression of ESE3/EHF in prostate cancer cells reduced stem-like potential and tumorigenicity. Analysis of gene expression profiling (GEP) data from three independent studies showed that the ESE3low tumours shared unique characteristics and displayed transcriptional features strikingly similar to transformed ESE3/EHF-knockdown prostate epithelial cells. Functional annotation and gene set enrichment analysis (GSEA) showed that ESE3low tumors were enriched of EMT and stem cell features. Furthermore, GSEA and unsupervised clustering indicated that ESE3low tumors retained prevalently expression of basal cell markers over luminal markers and displayed significant attenuation of androgen-induced genes compared to all other tumors. Interestingly, most of the ERG expressing tumors displayed opposite characteristics with expression of luminal markers. MicroRNA and lincRNA expression profiling also showed distinctive patterns between ESE3low tumors and the other tumors, while confirming the similarity with ESE3/EHF-knockdown cells. Collectively, these findings support a direct role of loss of ESE3/EHF expression in the pathogenesis of a subset of prostate tumors. Moreover, these data imply that distinct tumor subtypes can be indentified based on the expression of specific molecular marker that could reflect intrinsic differences in tumour biology and clinical evolution.
Citation Format: Maurizia Mello-Grand, Manuela Sarti, Gioacchino D'Ambrosio, Fausto Sessa, George Thalmann, Giovanna Chiorino, Carlo V. Catapano, Giuseppina MR Carbone, Domenico Albino, Vijay Kumar Singh, Gianluca Civenni, Nicole Longoni, Chiara Ghimenti, Paola Ostano, Sandra Pinton. Loss of expression of the endogenous ETS factor ESE3/EHF is associated with a distinct tumor subtype with stem-like and basal cell features [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B24.