TY - JOUR
T1 - Deoxycholate, an endogenous tumor promoter and DNA damaging agent, modulates BRCA-1 expression in apoptosis-sensitive epithelial cells
T2 - Loss of BRCA-1 expression in colonic adenocarcinomas
AU - Romagnolo, Donato F.
AU - Chirnomas, Ryan B.
AU - Ku, Jennifer
AU - Jeffy, Brandon D.
AU - Payne, Claire M.
AU - Holubec, Hana
AU - Ramsey, Lois
AU - Bernstein, Harris
AU - Bernstein, Carol
AU - Kunke, Kathleen
AU - Bhattacharyya, Achyut
AU - Warneke, James
AU - Garewal, Harinder
N1 - Funding Information:
This work was supported by NIH Program Project Grant CA72008, Arizona Disease Control Research Commission Grants 10016 and 6002, NIH Institutional Core Grant CA23074, NIEHS Grant ES06694, NIH Grants CA43894 and CA65579, VAH Merit Review Grant 2HG, Biomedical Diagnostics & Research, Inc., Tucson, AZ, Army Medical Research and Materiel Command Grant DAM D17-00-1-0130, and Graduate Training Program in Environmental Toxicology Grant ES-07091-22. Address correspondence to H. Bernstein, Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson, AZ 85724. Phone: (520) 626-6069. FAX: (520) 626-2100. E-mail: [email protected].
PY - 2003
Y1 - 2003
N2 - Deoxycholate, a bile salt present at high levels in the colonic lumen of individuals on a high-fat diet, is a promoter of colon cancer. Deoxycholate also causes DNA damage. BRCA-1 functions in repair of DNA and in induction of apoptosis. We show that, when cultured cells of colonic origin are exposed to deoxycholate at different concentrations, BRCA-1 expression is induced at a low noncytotoxic concentration (10 μM) but is strongly inhibited at higher cytotoxic concentrations (≥ 100 μM). Indication of phosphorylation of BRCA-1 by deoxycholate (100 μM) at a lower dose was seen by Western blot analysis, whereas, at a higher dose, deoxycholate (200 and 300 μM) caused a complete loss of BRCA-1 expression. We show that BRCA-1 is substantially lower in colon adenocarcinomas from five patients compared with associated non-neoplastic colon tissue from the same patients, suggesting that the loss of BRCA-1 expression contributes to the malignant phenotype. In the non-neoplastic colon tissue, BRCA-1 was localized to the nongoblet cells. Our results imply that reduced expression of BRCA-1 may be associated with carcinoma of the colon.
AB - Deoxycholate, a bile salt present at high levels in the colonic lumen of individuals on a high-fat diet, is a promoter of colon cancer. Deoxycholate also causes DNA damage. BRCA-1 functions in repair of DNA and in induction of apoptosis. We show that, when cultured cells of colonic origin are exposed to deoxycholate at different concentrations, BRCA-1 expression is induced at a low noncytotoxic concentration (10 μM) but is strongly inhibited at higher cytotoxic concentrations (≥ 100 μM). Indication of phosphorylation of BRCA-1 by deoxycholate (100 μM) at a lower dose was seen by Western blot analysis, whereas, at a higher dose, deoxycholate (200 and 300 μM) caused a complete loss of BRCA-1 expression. We show that BRCA-1 is substantially lower in colon adenocarcinomas from five patients compared with associated non-neoplastic colon tissue from the same patients, suggesting that the loss of BRCA-1 expression contributes to the malignant phenotype. In the non-neoplastic colon tissue, BRCA-1 was localized to the nongoblet cells. Our results imply that reduced expression of BRCA-1 may be associated with carcinoma of the colon.
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U2 - 10.1207/S15327914NC4601_11
DO - 10.1207/S15327914NC4601_11
M3 - Article
C2 - 12925308
AN - SCOPUS:10744225648
SN - 0163-5581
VL - 46
SP - 82
EP - 92
JO - Nutrition and cancer
JF - Nutrition and cancer
IS - 1
ER -