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 D(3) (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 this 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 differences 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.

Figure 1. Tumor progression of LPB-Tag prostate tumors in VDRWT and VDRKO animals unsupplemented and supplemented with exogenous testosterone

Sections were stained with hematoxylin and eosin (A) and progression was scored by modified Gleason Score (MGS) as described in materials and methods. Tumors initiate earlier in animals with testosterone supplementation (B). Animals expressing the VDR show inhibition of tumor progression in the absence of testosterone, but this protection is lost in the presence of exogenous testosterone. [●––● VDRWT/Tag +T; ■––■ VDRKO/Tag +T; ●– –● VDRWT/Tag -T; ■– –■ VDRKO/Tag -T; ▲––▲VDRKO/NT +T, ◆––◆ VDRKO/NT -T]

Figure 2. Quantitation of TUNEL and PCNA staining in VDRWT and VDRKO tumors after exogenous testosterone supplementation

Sections were stained with TUNEL or PCNA and percent of positive-stained cells was quantified as described in materials and methods. Values shown are mean ± SE (n=3, * indicates p<0.05). [■ VDRWT PCNA; □ VDRKO PCNA; VDR2WT TUNEL; VDRKO TUNEL]