Vitamin D Signaling Suppresses Early Prostate Carcinogenesis in TgAPT121 Mice.
Cancer Prev Res (Phila), 2019/06;12(6):343-356.
Fleet JC[1, 2], Kovalenko PL[3], Li Y[3], Smolinski J[4], Spees C[4], Yu JG[4], Thomas-Ahner JM[4], Cui M[3], Neme A[5], Carlberg C[6], Clinton SK[4, 7]
Affiliations
PMID: 31028080DOI: 10.1158/1940-6207.CAPR-18-0401
Impact factor: 3.296
Abstract
We tested whether lifelong modification of vitamin D signaling can alter the progression of early prostate carcinogenesis in studies using mice that develop high-grade prostatic intraepithelial neoplasia that is similar to humans. Two tissue-limited models showed that prostate vitamin D receptor (VDR) loss increased prostate carcinogenesis. In another study, we fed diets with three vitamin D3 levels (inadequate = 25 IU/kg diet, adequate for bone health = 150 IU/kg, or high = 1,000 IU/kg) and two calcium levels (adequate for bone health = 0.5% and high = 1.5%). Dietary vitamin D caused a dose-dependent increase in serum 25-hydroxyvitamin D levels and a reduction in the percentage of mice with adenocarcinoma but did not improve bone mass. In contrast, high calcium suppressed serum 1,25-dihydroxyvitamin D levels and improved bone mass but increased the incidence of adenocarcinoma. Analysis of the VDR cistrome in RWPE1 prostate epithelial cells revealed vitamin D-mediated regulation of multiple cancer-relevant pathways. Our data support the hypothesis that the loss of vitamin D signaling accelerates the early stages of prostate carcinogenesis, and our results suggest that different dietary requirements may be needed to support prostate health or maximize bone mass. SIGNIFICANCE: This work shows that disrupting vitamin D signaling through diet or genetic deletion increases early prostate carcinogenesis through multiple pathways. Higher-diet vitamin D levels are needed for cancer than bone.
MeSH terms
Adenocarcinoma; Animals; Apoptosis; Carcinogenesis; Cell Proliferation; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Prostatic Neoplasms; Receptors, Calcitriol; Signal Transduction; Tumor Cells, Cultured; Vitamin D; Vitamins
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