Abstract 813: Deletion of vitamin D receptor in prostate epithelial cells increases proliferation, reduces apoptosis, and enhances early carcinogenesis in the TgAPT121 mouse model of prostate cancer

High vitamin D status has been proposed to prevent prostate cancer (PCa). In vitro, the active metabolite of vitamin D suppresses PCa cell growth and has a number of other anti-cancer actions in prostate epithelial cells (PEC) that are mediated through a vitamin D receptor (VDR)-dependent transcriptional mechanism. We examined the in vivo importance of VDR in normal PEC biology and in PCa development using mouse models. In the first study, 7 wk-old wild type mice and mice with PEC-specific deletion of VDR (PEC-VDR KO) were randomized to intact, castration, or castration + testosterone propionate (TP, 2.5 mg/kg BW for last 5 d) groups and mice were killed 12 d later. PEC proliferation (Ki-67) and apoptosis (TUNEL) were determined in the anterior prostate (AP). Castration reduced proliferation and increased apoptosis indices in the prostate while TP treatment reversed these effects. In PEC-VDR KO mice, TUNEL staining was significantly reduced (e.g. 50% lower after castration) and Ki-67 staining was significantly increased (e.g. 2-fold higher after castration + TP) compared to the controls. This suggests that loss of VDR signaling provides an environment in the prostate that may be permissive to events that enhance prostate carcinogenesis. We tested this hypothesis in the TgAPT 121 transgenic mouse model of PCa. The TgAPT 121 transgenic mice express a truncated SV40 Large T antigen (T 121 ) in PEC. T 121 expression inactivates the retinoblastoma (Rb) family of proteins causing epithelial cell hyperplasia, development of prostatic intraepithelial neoplasia (PIN) lesions by 12 wk of age, and microinvasive adenocarcinoma by 6 mo of age. TgAPT 121 (APT;VDR WT) mice and TgAPT 121 lacking both VDR alleles in PEC (APT;PEC-VDR KO) were generated and at 28 wks of age their prostates were removed and histologically graded. The total area covered by high grade PIN, adenocarcinoma, and microinvasive cancer was significantly higher in APT;PEC-VDR KO as was the number of foci per AP for each of these lesions (e.g. adenocarcinoma lesion foci 7.93% in APT;PEC-VDR KO versus 2.55% in APT;VDR WT, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 813. doi:10.1158/1538-7445.AM2011-813