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.
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.
Romagnolo
Donato F
DF
Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85724, USA.
Chirnomas
Ryan B
RB
Ku
Jennifer
J
Jeffy
Brandon D
BD
Payne
Claire M
CM
Holubec
Hana
H
Ramsey
Lois
L
Bernstein
Harris
H
Bernstein
Carol
C
Kunke
Kathleen
K
Bhattacharyya
Achyut
A
Warneke
James
J
Garewal
Harinder
H
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
D002273:Carcinogens; D003902:Detergents; D003840:Deoxycholic Acid