HER2/Neu- and TAK1-mediated up-regulation of the transforming growth factor β inhibitor Smad7 via the ETS protein ER81

The cytokine transforming growth factor beta (TGF-beta) plays an important role in preventing tumor formation by blocking cell cycle progression. Accordingly, many cancers demonstrate mutations in TGF-beta signaling components or enhanced expression of inhibitors of the TGF-beta pathway such as Smad7. In this report we show that the oncoprotein HER2/Neu is able to collaborate with the ETS transcription factor ER81 to activate Smad7 transcription in breast, endometrial, and ovarian cancer cell lines. ER81 binds to two ETS sites within the Smad7 promoter, and mutation of one of these ETS sites greatly decreases Smad7 induction by HER2/Neu and ER81. Furthermore, we show that Smad7 activation involves the processing of signals from HER2/Neu to ER81 via the ERK mitogen-activated protein kinase pathway. Thus, we have uncovered a novel mechanism by which oncogenic HER2/Neu, in collaboration with ER81, can induce carcinogenesis through Smad7 upregulation. Moreover, we show that TAK1, a TGF-beta-activated protein kinase, stimulates ER81 via the p38 mitogen-activated protein kinase pathway and thereby induces the Smad7 promoter. This suggests that attenuation of TGF-beta signaling by activating Smad7 transcription may proceed not only through TGF-beta receptor-regulated Smad proteins but also through an independent pathway involving ER81 and TAK1.