Abstract LB-174: Enhanced prostate tumorigenesis in TgAPT121 mice lacking prostatic VDR expression

Population and cell-based work support the hypothesis that vitamin D has anti-cancer effects. We have previously reported that dietary vitamin D deficiency increases prostate epithelial cell proliferation and reduces apoptosis in wild-type mice and leads to more advanced prostate intraepithelial neoplasia (PIN) lesions in a transgenic mouse model (TgAPT 121 ) of early-stage prostate cancer. Vitamin D action depends upon signaling through the vitamin D receptor (VDR) and we have recently discovered that the prostate VDR mRNA and protein levels are elevated in TgAPT 121 PIN lesions. To determine the importance of VDR in prostate cancer prevention we deleted the VDR gene in TgAPT 121 mice and examined the impact on cancer development. Two different models were used to delete the VDR gene. In study 1, we made a triple transgenic mouse line with prostate epithelial cell-specific deletion of VDR: TgAPT 121 ; VDR flox/flox ; probasin-Cre +/− (PS-VDR KO, n = 32) and TgAPT 121 ; VDR flox/flox ; probasin-Cre −/− controls (n = 33). In study 2, we crossed TgAPT 121 mice with global VDR knockout mice whose abnormal calcium metabolism was corrected by intestinal-specific expression of human VDR (HV2) to generate the TgAPT 121 ; HV2 +/− , VDR −/− mice (HV2-VDR KO, n = 23) and TgAPT 121 ; HV2 +/− , VDR +/− controls (n = 27). HV2-VDR KO mice lack VDR in all cells of the prostate. Mice in both studies were provided with 1000 IU vitamin D 3 /kg diet from weaning until 6.5-mo of age at which time the prostates were harvested and processed for histology. HE p = 0.012). Similar results were found in Study 2 where HV2-VDR KO mice had higher Ad incidence, more Ad foci, and larger Ad focus size, as well as higher mean disease score than controls (31.8 vs. 29.9, p = 0.027). In addition, more PINIV and Mic foci were found in HV2-VDR KO mice than controls (p 121 mice, supporting the hypothesis that VDR is essential for vitamin D-mediated prostate cancer prevention. Supported by NIH Award CA101113 (JCF and SKC), NCI Cancer Prevention Interdisciplinary Education Program (YL), and Purdue Center for Cancer Research (JCF). 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 LB-174. doi:1538-7445.AM2012-LB-174