title: 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.
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 adenomatous polyposis coli (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 D(3) 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 D(3)-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 D(3)-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 (i) that calcium and vitamin D modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms, (ii) calcium and vitamin D as potential chemopreventive agents against colorectal neoplasms, and (iii) the potential of APC, β-catenin, and E-cadherin expression as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.
authors.affiliation: Nutrition and Health Sciences Program, Graduate Division of Biological and Biomedical Sciences, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Ahearn
authors.forename: Aasma
authors.initials: A
authors.lastname: Shaukat
authors.forename: W Dana
authors.initials: WD
authors.lastname: Flanders
authors.forename: Robin E
authors.initials: RE
authors.lastname: Rutherford
authors.forename: Roberd M
authors.initials: RM
authors.lastname: Bostick
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000328:Adult; D000368:Aged; D015820:Cadherins / Q000378:metabolism; D002136:Calcium, Dietary / Q000008:administration & dosage*; D002762:Cholecalciferol / Q000008:administration & dosage* / Q000097:blood; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019587:Dietary Supplements; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D015820:Cadherins; D002136:Calcium, Dietary; D051176:beta Catenin; D002762:Cholecalciferol