Abstract 2863: TMPRSS2-ERG influences IGF-1R expression and affects its prognostic value in prostate cancer

Abstract

Abstract INTRODUCTION: Insulin like growth factor 1 receptor (IGF-1R) plays a critical role in different tumors including prostate cancer (PCa). Recently, a fusion gene involving the androgen receptor-regulated gene TMPRSS2 and one of the ETS transcription factors family member, predominantly ERG, has been described in half of PCa patients. TMPRSS2-ERG results in the overproduction of a truncated ERG protein and cooperates in the establishment of a neoplastic phenotype in prostate cells. The aim of this study was to evaluate TMPRSS2-ERG impact on IGF-1R expression and to verify the value of IGF-1R as biomarker of PCa progression. MATERIAL AND METHODS: IGF-1R expression was evaluated in a panel of six prostate cell lines, including malignant VCaP, DU-145, PC-3, LNCaP, 22RV1 and non malignant RWPE-1 prostate cells by qRT-PCR, western blot and immunofluorescence. ERG siRNA was transiently transfected in VCaP cells and ERG down-regulation was assessed by western blot. Total RNA was extracted from a cohort of 270 paraffin-embedded PCa samples with more than 5 years of follow-up and IGF-1R expression was analysed by qRT-PCR. The prognostic value of IGF-1R was evaluated both in the univariate and multivariate analysis. The clinicopathological informations as well as the TMPRSS2-ERG fusion gene status were considered in the statistical analysis. RESULTS: The IGF-1R expression profile analysis was performed in PCa cells and pointed out that VCaP cell line, harboring the TMPRSS2-ERG fusion gene, carries the highest IGF-1R expression levels both considering mRNA, total protein and membrane expression levels. Interestingly, IGF-1R protein levels were found to be down-regulated upon ERG silencing in VCaP cells. PCa tumors did not show any remarkable difference in the expression of IGF-1R when compared with normal tissues (median=1.04) but IGF-1R was directly correlated with TMPRSS2-ERG status (p=0.027) in tumors. Log-rank tests showed an association between higher IGF-1R expression and better biochemical progression free survival (p=0.047).When dividing the population according to the TMPRSS2-ERG status we found higher fold-change in IGF-1R expression in tumors expressing TMPRSS2-ERG (median=1.25) compared to non-expressors (median=0.91) and a statistically stronger association between IGF-1R and prognosis in the TMPRSS2-ERG negative tumors (p=0.012). Moreover, multivariate analysis confirmed that higher expression of IGF-1R is an independent indicator of better prognosis in this subgroup (HR:0.48.IC95% [0.25-0.90].p=0.023). CONCLUSIONS: In this study we demonstrated that TMPRSS2-ERG affects IGF-1R expression both in vitro and in clinical samples. High expression of IGF-1R is significantly associated with a better clinical outcome of PCa patients. (Grants: FIRB RBAP11884M_005 to KS; FIS PI10/01206 and FPI11/00505 from ISCIII) Citation Format: Caterina Mancarella, Irene Casanova-Salas, Josè Antonio Lopez-Guerrero, Katia Scotlandi. TMPRSS2-ERG influences IGF-1R expression and affects its prognostic value in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2863. doi:10.1158/1538-7445.AM2014-2863