ETV4 overexpression cooperates with Pten deletion for prostate cancer progression in mice.

Introduction Half of cases of Prostate cancer (PC) carry a chromosomal translocation involving one of the genes of the ETS family (ERG, ETV1, ETV4, ETV5, FLI1). Each translocation results in the deregulated expression of an ETS protein in the prostate that, likely, plays a direct role in PC pathogenesis. We have showed that in prostate cell lines ETV4 overexpression increases migration and invasion, and also proliferation, cell cycle progression, anchorage-independent growth, tumor growth in xenograft model. Here we have investigated the effects of ETV4 expression in mouse prostate. Material and Methods The truncated form of ETV4, present in patients, has been cloned under the control a modified rat probasin gene promoter that drives prostate specific expression. By using this construct we have obtained two different transgenic mouse lines with ETV4 specific prostate expression (ETV4-FVB mice). The tissues of these mice have been analyzed by H&E staining and immunohistochemistry. Result and discussion 6 months-old (mo) ETV4-FVB mice did not present prostate lesions, whereas low grade prostatic intraepithelial neoplasia (LGPIN) lesions have been found in about half of 10 mo mice (10 of 18 line C, 4 of 11 line E) and in none of control mice. Since Pten loss is common in PC and it is often associated with ETS translocations, we have investigated the interaction of ETV4 expression with Pten loss by crossing our FVB-ETV4 mice with PTEN+/- mice. Analyzing the progeny of this cross at 7 months of age we found LGPIN in 33% of FVB-ETV4 mice and in 50% of Pten+/- mice, whereas we found multifocal high grade PIN (HGPIN) lesions in all Pten+/-,ETV4 mice (n=9). In addition, at least one LGPIN was found in all 2 months-old Pten+/-,ETV4. Thus, Pten+/-,ETV4 developed early neoplastic lesions whose number and severity increased with age: in fact, HGPIN progressed to locally invasive adenocarcinoma in 12.5% of 7 mo mice and in 50% 10 mo mice. Conclusion These results suggest that ETV4 over-expression is sufficient to initiate neoplastic transformation and cooperates with Pten loss in promoting prostate cancer progression. Thus, also in vivo, ETV4 induces most and perhaps all of the features that make a tumor. Now we are investigating the molecular mechanisms through which ETV4 cooperates with Pten loss to promote cancer progression. These mouse models, in addition to provide insight into PC biology, will be useful to test the effectiveness of experimental therapeutic approaches.