Over-expression of ERT(ESX/ESE-1/ELF3), an ets-related transcription factor, induces endogenous TGF-beta type II receptor expression and restores theTGF-beta signaling pathway in Hs578t human breast cancer cells

The epithelium-specific transcription factor, ERT/ESX/ ESE-1/ELF3, binds to the TGF-beta RII promoter in a sequence specific manner and regulates its expression, In this study, we investigated whether ERT could regulate endog enous TGF-beta RII expression in Hs578t breast cancer cells. Analyses of th e Hs578t parental cell line revealed ion RII mRNA expression and resistance to the growth inhibitory effects of TGF-beta. Infection of this cell Line with a retroviral construct expressing ERT induced higher levels of endogen ous RII mRNA expression and protein expression relative to cells infected w ith chloramphenicol acetyltransferase (CATneo) as a control. Relative to co ntrol cells, the ERTneo-expressing Hs578t cells show approximately a 50% re duction in cell growth in the presence of exogenous TGF-beta 1, as well as a fourfold higher induction of activation in transient transfection assays using the 3TP-luciferase reporter construct. When transplanted into athymic mice, ERT-expressing Hs578t cells showed decreased and delayed tumorigenic ity compared with control cells. This data strongly suggests that ERT plays an important role as a transcriptional activator of TGF-P RII expression, and that deregulated ERT expression may play a critical role in rendering H s578t human breast cancer cells insensitive to TGF-beta's growth inhibitory effects.