Effects of calcium and vitamin D on MLH1 and MSH2 expression in rectal mucosaof sporadic colorectal adenoma patients

• Type of Material: Article
• Authors: Eduard Sidelnikov, Emory University; Roberd M Bostick, Emory University; W Dana Flanders, Emory University; Qi Long, Emory University; Veronika Fedirko, Emory University; Aasma Shaukat, University of Minnesota; Carrie R. Daniel, Department of Health and Human Services; Robin E Rutherford, Emory University
• Language: English
• Date: 2010-04
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: @ 2013 Society for Endocrinology
• Final Published Version (URL): http://cebp.aacrjournals.org/content/19/4/1022
• Title of Journal or Parent Work: Cancer Epidemiology, Biomarkers and Prevention
• ISSN: 1055-9965
• Volume: 19
• Issue: 4
• Start Page: 1022
• End Page: 1032
• Grant/Funding Information: Franklin Foundation; Georgia Cancer Coalition Distinguished Scholar award (R.M. Bostick); National Cancer Institute, NIH R01 CA104637 (R.M. Bostick)
• Keywords: mutS-homolog 2 (MSH2); randomized controlled trial; normal colorectal mucosa; DNA mismatch repair; mutL-homolog 1 (MLH1)
• Research Categories: Health Sciences, Oncology; Health Sciences, Epidemiology; Health Sciences, Public Health

Abstract

To further clarify and develop calcium and vitamin D as chemopreventive agents against colorectal cancer in humans and develop modifiable biomarkers of risk for colorectal cancer, we conducted a pilot, randomized, double-blind, placebo-controlled, 2×2 factorial clinical trial to test the effects of calcium and vitamin D3, alone and in combination on key DNA mismatch repair proteins in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2.0 g/d calcium or 800 IU/d vitamin D3, alone or in combination, versus placebo over six months. Colorectal crypt overall expression and distribution of MSH2 and MLH1 proteins in biopsies of normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. After six months of treatment MSH2 expression along the full lengths of crypts increased by 61% (p=0.11) and 30% (p=0.36) in the vitamin D and calcium groups, respectively, relative to the placebo group. The estimated calcium and vitamin D treatment effects were more pronounced in the upper 40% of crypts (differentiation zone) where MSH2 expression increased by 169% (p=0.04) and 107% (p=0.13) in the vitamin D and calcium groups, respectively. These findings suggest that higher calcium and vitamin D intakes may result in increased DNA MMR system activity in the normal colorectal mucosa of sporadic adenoma patients, and that the strongest effects may be vitamin D related and in the differentiation zone of the colorectal crypt.