Regulation of C-myc Gene Expression by Potassium Channel Blocker Quinidine in MCF-7 Human Breast Cancer Cell Line

摘要

C-MYC IS ONE OF THE MOST COMMON ONCOGENE ABERRATIONS IN BREAST CANCER, SUGGESTING ITS IMPORTANT ROLE IN THE GENESIS AND/OR PROGRESSION OF BREAST CANCER. Therefore, it is critical to elucidate the precise molecular mechanisms of c-myc gene regulation. The goal of this proposal was to understand how potassium channel blocker, quinidine, regulates expression of c-myc oncogene in human breast cancer cells. We found that quinidine significantly suppressed c-myc promoter activity and a 168 bp region of human c-myc promoter, a quinidine response region (-100 to +68 with respect to the Pt) is sufficient to confer responsiveness to quinidine. In addition, quinidine suppressed c-myc mRNA and protein levels in four human breast cancer but not normal breast epithelial cell lines. Suppression of Myc by quinidine paralleled by inhibition of growth and induction of a more differentiated phenotype in breast cancer cells. The preferential suppression of c-myc and induction of differentiation in tumor but not normal breast epithelial cells is very interesting and exciting finding. Quinidine is a potential lead compound for developing pharmacological agents to regulate Myc. In addition, the study of quinidine-regulated events is a promising approach to unravel differentiation control pathways that become disrupted in breast cancer.