A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients

• Authors: Thomas U. Ahearn, Emory University; Aasma Shaukat, University of Minnesota; W Dana Flanders, Emory University; Robin E Rutherford, Emory University; Roberd M Bostick, Emory University
• Journal Title: Cancer Prevention Research
• Volume: Volume 5, Number 10
• Publisher: American Association for Cancer Research | 2012-10, Pages 1247-1256
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/1940-6207.CAPR-12-0292
• Subjects: Health Sciences, Oncology; Health Sciences, Nutrition; Biology, Biostatistics
• Keywords: calcium; vitamin D; colonic neoplasms; biomarkers; clinical trial

Abstract

APC/β-catenin pathway perturbation is a common early event in colorectal carcinogenesis and is affected by calcium and vitamin D in basic science studies. To assess the effects of calcium and vitamin D on APC, β-catenin, and E-cadherin expression in the normal appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a randomized, double-blinded, placebo-controlled 2×2 factorial clinical trial. Pathology-confirmed colorectal adenoma cases were treated with 2 g/day elemental calcium and/or 800 IU/day vitamin D3 versus placebo over 6 months (N=92; 23/group). Overall APC, β-catenin, and E-cadherin expression and distributions in colon crypts in normal-appearing rectal mucosa biopsies were detected by standardized automated immunohistochemistry and quantified by image analysis. In the vitamin D3-supplemented group relative to placebo, the proportion of APC in the upper 40% of crypts (ϕh APC) increased 21% (p=0.01), β-catenin decreased 12% (p=0.18), E-cadherin increased 72% (p=0.03), and the ϕh APC/β-catenin ratio (APC/β-catenin score) increased 31% (p=0.02). In the calcium-supplemented group ϕh APC increased 10% (p=0.12), β-catenin decreased 15% (p=0.08), and the APC/β-catenin score increased 41% (p=0.01). In the calcium/vitamin D3 supplemented group β-catenin decreased 11% (p=0.20), E-cadherin increased 51% (p=0.08), and the APC/β-catenin score increased 16% (p=0.26). These results support 1) that calcium and vitamin D modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms, 2) calcium and vitamin D as potential chemopreventive agents against colorectal neoplasms, and 3) the potential of APC, β-catenin, and E-cadherin expression as modifiable, pre-neoplastic risk biomarkers for colorectal neoplasms.