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 a 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.