title: Deoxycholate, an endogenous tumor promoter and DNA damaging agent, modulates BRCA-1 expression in apoptosis-sensitive epithelial cells: loss of BRCA-1 expression in colonic adenocarcinomas.
abstract: 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 microM) but is strongly inhibited at higher cytotoxic concentrations ( > or =100 microM). Indication of phosphorylation of BRCA-1 by deoxycholate (100 microM) at a lower dose was seen by Western blot analysis, whereas, at a higher dose, deoxycholate (200 and 300 microM) 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.
authors.affiliation: Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Donato F
authors.initials: DF
authors.lastname: Romagnolo
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Chirnomas
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ku
authors.forename: Brandon D
authors.initials: BD
authors.lastname: Jeffy
authors.forename: Claire M
authors.initials: CM
authors.lastname: Payne
authors.forename: Hana
authors.initials: H
authors.lastname: Holubec
authors.forename: Lois
authors.initials: L
authors.lastname: Ramsey
authors.forename: Harris
authors.initials: H
authors.lastname: Bernstein
authors.forename: Carol
authors.initials: C
authors.lastname: Bernstein
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kunke
authors.forename: Achyut
authors.initials: A
authors.lastname: Bhattacharyya
authors.forename: James
authors.initials: J
authors.lastname: Warneke
authors.forename: Harinder
authors.initials: H
authors.lastname: Garewal
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage; D003840:Deoxycholic Acid / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D019398:Genes, BRCA1 / Q000187:drug effects*; D006801:Humans; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D002273:Carcinogens; D003902:Detergents; D003840:Deoxycholic Acid