Abstract LB-174: Enhanced prostate tumorigenesis in TgAPT121 mice lacking prostatic VDR expression
Authors: Yan Li, Pavlo L. Kovalenko, Steven K. Clinton, James C. Fleet
Journal: Cancer Research (2012)

Abstract 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 (TgAPT121) 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 TgAPT121 PIN lesions. To determine the importance of VDR in prostate cancer prevention we deleted the VDR gene in TgAPT121 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: TgAPT121; VDRflox/flox; probasin-Cre+/− (PS-VDR KO, n = 32) and TgAPT121; VDRflox/flox; probasin-Cre−/− controls (n = 33). In study 2, we crossed TgAPT121 mice with global VDR knockout mice whose abnormal calcium metabolism was corrected by intestinal-specific expression of human VDR (HV2) to generate the TgAPT121; HV2+/−, VDR−/− mice (HV2-VDR KO, n = 23) and TgAPT121; 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 D3/kg diet from weaning until 6.5-mo of age at which time the prostates were harvested and processed for histology. H&amp;E-stained sections of the anterior lobes were examined using a grading system established based on the spectrum of prostate phenotypes in TgAPT121 mice: hyperplasia, four levels of PIN lesions (PIN I-PIN IV), microinvasive lesion (Mic), and well-differentiated adenocarcinoma (Ad). A disease score was calculated for each mouse based on the prevalence of its two most severe lesion types, with a higher score indicating more advanced cancer. In study 1, twice as many PS-VDR KO mice developed Ad compared to control (73% vs. 38%, p = 0.004). On average, the PS-VDR KO mice had more Ad foci (p = 0.003) and the size of each focus was larger (p = 0.005) when compared with controls. Consistent with the grading data, mean disease score was significantly higher in PS-VDR KO mice (32.2 vs. 30.7; 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 &amp;lt; 0.05). Together these results show that disrupted VDR expression increases prostate cancer development in TgAPT121 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