VDR ablation alters basal gene expression and exacerbates AOM‐induced aberrant crypt foci in colon of C57 female mice

Nuclear receptors (NR), such as the vitamin D receptor (VDR) play a crucial role in modulating cell proliferation and differentiation. We hypothesized that ablation of the VDR may increase risks of azoxymethane (AOM)‐induced colon carcinogenesis. We injected wild type (WT) or VDR knock out (VDRKO) 1 year old female mice with AOM or saline once a week for 4 weeks and quantitated number and size of colonic aberrant crypt foci (ACF) 6 weeks later. Using a multiple comparison test, we found that AOM treatment significantly increased the number of ACF per animal compared to control in both genotypes. In addition, VDRKO AOM treated animals had significantly more ACF (3.5) compared to their WT counterparts (2.2; p<0.05) while no difference were observed between untreated groups (p>0.05). Using real time PCR, we analyzed baseline gene transcription in the colon and liver of WT and VDRKO untreated animals. VDRKO mice had significantly greater p21 expression while CYP3A11 levels were significantly reduced in both organs compared to WT animals. PXR, a NR which induces CYP3A11, was significantly reduced in liver, while PPARγ was significantly elevated in colon of VDRKO animals. These significant changes at baseline suggest alterations in drug metabolism and/or cell cycle that may increase risk for colon carcinogenesis in the absence of VDR.