Truncated ETV1, Fused to Novel Tissue-Specific Genes, and Full-Length ETV1 in Prostate Cancer

Abstract

In this study, we describe the properties of novel ETV1 fusion genes, encoding N-truncated ETV1 (dETV1), and of full-length ETV1, overexpressed in clinical prostate cancer. We detected overexpression of novel ETV1 fusion genes or of full-length ETV1 in 10% of prostate cancers. Novel ETV1 fusion partners included FOXP1, an EST (EST14 ), and an endogenous retroviral repeat sequence (HERVK17). Like TMPRSS2, EST14 and HERVK17 were prostate-specific and androgen-regulated expressed. This unique expression pattern of most ETV1 fusion partners seems an important determinant in prostate cancer development. In transient reporter assays, full-length ETV1 was a strong transactivator, whereas dETV1 was not. However, several of the biological properties of dETV1 and full-length ETV1 were identical. On stable overexpression, both induced migration and invasion of immortalized nontumorigenic PNT2C2 prostate epithelial cells. In contrast to dETV1, full-length ETV1 also induced anchorage-independent growth of these cells. PNT2C2 cells stably transfected with dETV1 or full-length ETV1 expression constructs showed small differences in induced expression of target genes. Many genes involved in tumor invasion/metastasis, including uPA/uPAR and MMPs, were up-regulated in both cell types. Integrin B3 (ITGB3) was clearly up-regulated by full-length ETV1 but much less by dETV1. Based on the present data and on previous findings, a novel concept of the role of dETV1 and of full-length ETV1 overexpression in prostate cancer is proposed. [Cancer Res 2008;68(18):7541-9]

ETS fusion genes in prostate cancer

“…ETV1 is overexpressed in 5-10% of prostate cancers (Tomlins et al 2005, Hermans et al 2008a. ETV1 gene fusions lead to overexpression of a truncated ETV1 protein that lacks the N-terminal TAD domain (Fig.…”

“…ETS gene fusions in prostate cancer seem mutually exclusive, but in multifocal disease more than one fusion event can be found. ERG is predominantly fused to TMPRSS2, but ETV1, ETV4, and ETV5 have multiple fusion partners that all are located on different chromosomes (Table 1; Tomlins et al 2006, 2007, Attard et al 2008a, Han et al 2008, Helgeson et al 2008, Hermans et al 2008a,b, Clark & Cooper 2009, Rubin et al 2011. Interestingly, two of the fusion partners are endogenous retroviral HERV-K sequences that are apparently insignificant in the normal prostate.…”

“…ETV1 is overexpressed not only as a fusion gene but also as a full-length mRNA, due to translocation of the complete gene , Hermans et al 2008a, Gasi et al 2011. Several full-length ETV1 translocations are to a specific region of chromosome 14 that also contains EST14.…”

“…ETS overexpression alone seems insufficient to induce prostate cancer. In vitro studies showed that overexpression of ERG or ETV1 in immortalized, non-tumorigenic epithelial prostate cells increased cell migration and invasion , Hermans et al 2008a, Klezovitch et al 2008, and knockdown of ERG or ETV1 in prostate cancer cell lines slowed invasion , Sun et al 2008. In genetically modified mice (GEMs), overexpression of ERG or ETV1 resulted in the development of PIN but not of invasive cancer (Klezovitch et al 2008, Tomlins et al 2008b).…”

ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples

“…2 To date, 14 genes (TMPRSS2, SLC45A3, HERV-K, KLK2, CANT1, FOXP1, HERVK17, EST14, FLJ35294, C15orf21, HNRPA2B1, DDX5, ACSL3 and NDRG1) have been identified as 5 0 fusion partners for the four ETS family transcription factor genes (ERG, ETV1, ETV4 and ETV5), resulting in 420 different fusion genes in prostate cancer. 2,3,4,5 Among these, approximately 90% occur between TMPRSS2 and ERG. 2 The association of the TMPRSS2:ERG gene fusion with prostate cancer prognosis has been evaluated in multiple studies but with contradictory results.…”