Abstract 655: Determination of the pro-oncogenic role of PIM1/PIM2 kinases in male reproductive system pre-neoplastic lesions by using conditional transgenic murine models

Background. PIM proteins belong to a family of ser/thr kinases composed of 3 members, PIM1, 2 and 3, with overlapping functions mainly regulated by pathways controlled by JAK/STAT transcription factors. The PIM family proteins have been implicated in the regulation of apoptosis, metabolism, cell cycle, homing and migration, and they have been found to be overexpressed in many sort of tumors, therefore these proteins are interesting targets for anticancer drug therapy. Although the PIM kinases have been identified as oncogenes in transgenic models, they have weak transforming abilities on their own. However, they have shown to enhance the capacity of other genes or chemical carcinogens to induce tumors. Germinal tumors are among the solid tumors in which both PIM1/2 proteins have been found to be overexpressed. Objetives. To study the causal role of PIM1/PIM2 proteins and the molecular machinery involved in the generation of male reproductive system tumors. Methods. We generated two CRE conditional transgenic mice with confined expression of human PIM1 or PIM2 in hormone-dependent tissues, due to MMTV gene promoter which expression is induced by steroid hormones. We fully characterized the hyperproliferative response to these genetic alterations in both TgPIM1 and TgPIM2 models. Results and conclusions. Conditional transgenic MMTV-Cre/PIM1 and MMTV-Cre/PIM2 models are useful in vivo murine models for studying initiation and progression processes of steroid-dependent tumor development, such as testicle, seminal vesicle and prostate neoplastic alterations. PIM1/2 models showed a reduced survival, a higher percentage of tumors at clinical endpoint and a higher incidence of total tumors percentage, noticing more statistically significant data of tumor incidence, possibly because PIM1/2 expression induces alterations in hormone-dependent tissues that increase proliferation rate and tissue atrophy of certain cyto-architectonic structures embedded in those tissues, leading to physiological mechanisms that shortens life. PIM1/2 conditional models generated hyperplastic changes in testicle and prostate tissues, and epithelial adenomas areas in seminal vesicles, but no carcinomas of male reproductive system, which indicates that PIM1/2 genes are involved in tumor initiation level, but require synergy effects with other oncogenes or carcinogens, which would explain low percentage of male reproductive system tumors registered and no carcinoma formation. Additionally, enhanced inflammation surrounding target tissues were found in PIM1/2 models, which it could be a tumor initiation mechanism led by PIM deregulation of cellular JAK/STAT signaling. Together our data indicate that PIM1/2 over-expression induces a pre-neoplastic phenotype in testicle, seminal vesicles and prostate, pointing a possible role in oncogenic initiation in these tissues. Citation Format: Antonio Lucena-Cacace, Manuel P Jimenez-Garcia, Irene Ferrer, Blanca Felipe Abrio, Eva M Verdugo-Sivianes, Daniel Otero Albiol, Marco Perez, Sandra Munoz-Galvan, Jose Manuel Garcia Heredia, Javier Peinado-Serrano, Juan Jose Marin, Maja Narlik-Grassow, Carmen Blanco-Aparicio, Amancio Carnero. Determination of the pro-oncogenic role of PIM1/PIM2 kinases in male reproductive system pre-neoplastic lesions by using conditional transgenic murine models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 655.