Reduced expression of c-erbB2 gene product in human mammary carcinoma SK-BR-3 cells treated with interferon-gamma and tumor necrosis factor-alpha.
Abnormalities in the expression, structure, or activity of proto-oncogene products have been implicated in the development and maintenance of the malignant cells. Proto-oncogene c-erbB2/HER2 gene product P185HER2 is one such regulatory cellular protein, elevated expression of which can result in transformed phenotypes of mouse fibroblast NIH3T3 cells, and has been also shown to be overexpressed in a number of human tumors including breast carcinoma. In the studies presented here, we have investigated the effects of antiproliferative cytokines such as interferons (INFs) and tumor necrosis factor-alpha (TNF-alpha) on the modulation of expression of P185HER2 and growth-rate of human mammary carcinoma SK-BR-3 cells which overexpress P185HER2. It was observed that the antiproliferative effects of IFN-gamma and TNF-alpha on the cultures of SK-BR-3 cells were associated with reduction in the steady-state levels of P185HER2 with no change in the steady state levels of expression of c-erbB2 mRNA. Treatment of SK-BR-3 cells with either IFN-gamma or TNF-alpha was accompanied by inhibition of rate of synthesis of the protein, enhanced turnover of newly synthesized P185HER2, and reduced expression of P185HER2 on the cell surface. These observed effects on the expression of P185HER2 were more pronounced by more growth inhibitory TNF-alpha than IFN-gamma. These observations suggest that the growth regulation of SK-BR-3 cells by IFN-gamma and TNF-alpha may be associated with reduced expression P185HER2.
Kumar
R
R
Department of Medicine, Pennsylvania State University College of Medicine, Hershey 17033.
Mendelsohn
J
J
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D066246:ErbB Receptors / Q000032:analysis* / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D066246:ErbB Receptors; D007371:Interferon-gamma; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C000715470:MAS1 protein, human