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 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.