Abstract 534: Protein kinase c ≤ cooperates with Pten deficiency in prostate cancer progression

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related deaths among men. Protein kinase C epsilon (PKC∈), a member of the PKC family of phorbol ester/diacylglycerol receptors, has been shown to be up-regulated in human prostate cancer specimens. We recently demonstrated that mice that specifically overexpress PKC∈ in prostate under the control of the probasin promoter (PB-PKC∈) develop hyperplasia and PIN lesions. However, PKC∈ overexpression was insufficient to drive neoplastic changes in the mouse prostate. In the present study our goal was to determine whether PKC∈ overexpression can cooperate with Pten deficiency, one of the most common genetic alterations in human prostate cancer. We stably overexpressed PKC∈ in two pairs of isogenic mouse prostate epithelial lines that are either heterozygous (P2, P8) or homozygous (CaP2, CaP8) for Pten deletion. PKC∈ overexpression led to significant enhancement in cell proliferation compared to the respective control cells and this effect is more pronounced in CaP2 or CaP8 cells. Moreover, assays of colony formation in liquid medium revealed that anchorage-dependent growth was augmented in PKC∈-overexpressing cells relative to control cells. A significant elevation in phospho-Akt levels was observed in PKC∈ overexpressing cells relative to respective controls. To further elucidate the cooperativity between PKC∈ overexpression and Pten loss we intercrossed the PB-PKC∈ transgenic mice and Pten+/− mice. Strikingly, the resulting compound mutant mice overexpressing PKC∈ and haploinsufficient for Pten (PB-PKC∈; Pten+/−) developed fully invasive adenocarcinoma at 12 months of age. Very strong phospho-Akt, phospho-S6 and phospho mTOR staining could be detected in adenocarcinomas from PB-PKC∈; Pten+/− mice. Furthermore, we detected enhanced p-Erk, Cox-2, STAT3, NF-κB and cyclin D1 signaling in adenocarcinomas from PB-PKC∈;Pten+/− mice than in lesions from each monogenic model. These data thus suggest that PKC∈ overexpression cooperates with a defined oncogenic input to promote prostate tumorigenesis. These findings also suggest a crucial role of PKC∈ in survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 534. doi:1538-7445.AM2012-534