ETS-1 oncogenic activity mediated by transforming growth factor α

Abstract

Inappropriate expression of Ets-1 is observed in a variety of human cancers, and its forced expression in cultured cells results in transformation, autonomous proliferation, and tumor formation. The basis by which Ets-1 confers autonomous growth, one of the primary hallmarks of cancer cells and a critical component of persistent proliferation, has yet to be fully explained. Using a variety of cancer cell lines, we show that inhibition of Ets-1 blocks tumor formation and cell proliferation in vivo and autonomous growth in culture. A screen of multiple diffusible growth factors revealed that inhibition of Ets-1 results in the specific down-regulation of transforming growth factor α (TGFα), the proximal promoter region of which contains multiple ETS family DNA binding sites that can be directly bound and regulated by Ets-1. Notably, rescuing TGFα expression in Ets-1-silenced cells was sufficient to restore tumor cell proliferation in vivo and autonomous growth in culture. These results reveal a previously unrecognized mechanism by which Ets-1 oncogenic activity can be explained in human cancer through its ability to regulate the important cellular mitogen TGFα. ©2010 AACR.