Tumor progression in the LPB-Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status

Abstract

Previous studies have suggested that 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) induces cell cycle arrest and/or apoptosis in prostate cancer cells in vitro, suggesting that vitamin D may be a useful adjuvant therapy for prostate cancer and a chemopreventive agent. Most epidemiological data however shows a weak link between serum 25(OH)D3 and risk of prostate cancer. To explore dichotomy we have compared tumor progression in the LPB-Tag model of prostate in VDR knock out (VDRKO) and wild type (VDRWT) mice. On the C57BL/6 background LPB-Tag tumors progress significantly more rapidly in the VDRKO mice. VDRKO tumors show significantly higher levels of cell proliferation than VDRWT tumors. In mice supplemented with testosterone to restore the serum levels to the normal range, these difference in tumor progression, and proliferation are abrogated, suggesting that there is considerable cross-talk between the androgen receptor (AR) and the vitamin D axis which is reflected in significant changes in steady state mRNA levels of the AR, PCNA, cdk2 survivin and IGFR1 and 2 genes. These alterations may explain the differences between the in vitro data and the epidemiological studies.

Contributions of Genetically Modified Mouse Models to Understanding the Physiology and Pathophysiology of the 25-Hydroxyvitamin D-1-Alpha Hydroxylase Enzyme (1α(OH)ase) and the Vitamin D Receptor (VDR)

“…More recently, VDR knockout mice were crossed with the LPB-Tag prostate cancer model. Prostate tumors progressed more rapidly in the VDR knockout animals compared to VDR wild-type animals [162]. These animal studies support a mechanism linking local substrate 25 (OH)D availability and tumor progression.…”

MECHANISMS IN ENDOCRINOLOGY: Vitamin D and fertility: a systematic review

“…It has been shown that androgens increase 1a-hydroxylase (43). Furthermore, it was demonstrated that the regulation of gene expression by vitamin D metabolites is modified according to androgen levels (114). These data may suggest that androgen deficiency could hypothetically amplify the adverse health consequences of vitamin D deficiency.…”

Cellular and molecular effects of vitamin D on carcinogenesis

“…Results indicated that LPB-Tag tumors progress more rapidly in Vdr null mice than in control animals, and tumors lacking VDR have higher levels of cell proliferation than those expressing VDR. Interestingly, supplementation of LPB-Tag mice with testosterone abrogates these differences in tumor progression and proliferation, indicating cross-talk between the androgen and the vitamin D signaling pathways [119]. This cross talk has been further studied in the TgAPT121 mouse model of PIN in which the impact of dietary vitamin D, Vdr deletion and castration were evaluated [70].…”