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: Donato F Romagnolo, Ryan B Chirnomas, Jennifer Ku, Brandon D Jeffy, Claire M Payne, Hana Holubec, Lois Ramsey, Harris Bernstein, Carol Bernstein, Kathleen Kunke, Achyut Bhattacharyya, James Warneke, Harinder Garewal
• Journal: Nutrition and cancer (Nutr Cancer) Vol. 46 Issue 1 Pg. 82-92 ( 2003) ISSN: 0163-5581 [Print] United States
• PMID: 12925308 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carcinogens
• Detergents
• Deoxycholic Acid

Topics

• Adenocarcinoma (genetics, pathology)
• Adult
• Aged
• Apoptosis (drug effects)
• Blotting, Western
• Carcinogens (pharmacology)
• Cell Survival (drug effects)
• Colonic Neoplasms (genetics, pathology)
• DNA Damage
• Deoxycholic Acid (pharmacology)
• Detergents (pharmacology)
• Epithelial Cells (drug effects, pathology)
• Gene Expression (drug effects)
• Genes, BRCA1 (drug effects)
• Humans
• Middle Aged
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured