Myc protein is differentially sensitive to quinidine in tumor versus immortalized breast epithelial cell lines.
Quinidine regulates growth and differentiation in human breast tumor cells, but the immortalized mammary epithelial MCF-10A cell line is insensitive to quinidine. We found that a morphologically similar differentiation response was evoked by quinidine and c-myc antisense oligonucleotides in MCF-7 cells and this prompted us to investigate the actions of quinidine on c-myc gene expression. Myc protein levels were suppressed in human breast tumor cell lines, but not in MCF-10A cells, an observation that supports the hypothesis that suppression of c-myc gene expression is involved in the preferential growth and differentiation response of breast tumor cells to quinidine. Quinidine reduced c-myc mRNA levels in MCF-7 cells. Acute induction of c-myc mRNA by estradiol, as well as the c-myc response to sub-cultivation in fresh serum and H-ras driven elevations in c-myc mRNA were depressed by 50-60% in the presence of quinidine. Quinidine decreased c-myc promoter activity in MCF-7 cells in a transient reporter gene assay and a 168 bp region of human c-myc promoter (-100 to +68 with respect to the P1 promoter) was sufficient to confer responsiveness to quinidine. 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.
D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011802:Quinidine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D011802:Quinidine