Targeting gene transcription: a new strategy to down-regulate c-erbB-2 expression in mammary carcinoma.
Overexpression of the c-erbB-2 proto-oncogene in mammary carcinoma is frequently associated with amplification of the c-erbB-2 gene, but it also occurs from single-copy gene. Studies in mammary-derived cell lines have shown that, whether or not the gene is amplified, there is a 6- to 8-fold increase in the accumulation of c-erbB-2 mRNA per gene copy in overexpressing cells. We have recently shown that this phenomenon is due to increased activity of the c-erbB-2 promoter mediated by the binding of a novel transcription factor, OB2-1, which is present at higher levels in overexpressing cells than in low expressors. OB2-1 activity therefore represents a novel therapeutic target for the down-regulation of c-erbB-2 levels in human cells. As a prototype for this strategy, we show here that the drug sodium aurothiomalate is able to inhibit the DNA-binding activity of OB2-1 in vitro and also to interfere with c-erbB-2 promoter activity in cell-based transfection assays. In addition, endogenous c-erbB-2 immunoreactivity was reduced in cells treated with aurothiomalate as compared with the levels observed in control cells.
Hollywood
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DP
Gene Transcription Laboratory, Hammersmith Hospital, London, UK.
Hurst
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HC
D001943:Breast Neoplasms; D002460:Cell Line; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006052:Gold Sodium Thiomalate / Q000494:pharmacology; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C081684:OB2-1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D014157:Transcription Factors; D006052:Gold Sodium Thiomalate