TGFbeta-regulated transcriptional mechanisms in cancer.

Transforming growth factor-beta (TGFbeta) has been implicated in oncogenesis for many years. The multifunctional activities of TGFbeta endow it with both tumor suppressor and tumor promoting activities, depending on the stage of carcinogenesis and the responsivity of the tumor cell. In early tumor stages, TGFbeta inhibits epithelial cell growth through induction of apoptosis and cell cycle arrest. During tumor development, however, many tumor cells lose their growth-inhibitory responses to TGFbeta owing to genetic alterations or signaling perturbations such as oncogenic Ras signaling. Loss of TGFbeta-growth inhibition is commonly associated with increased tumor cell invasion and metastasis of tumor cells that undergo an epithelial-mesenchymal transition. Interestingly, the tumor-promoting effects of TGFbeta on the tumor cells are observed particularly in cells in which TGFbeta-signaling remains functional despite loss of growth control by TGFbeta. New insights into transcriptional mechanisms activated by TGFbeta are providing a better understanding of the cellular changes involved in the switch of TGFbeta from a tumor suppressor to a tumor promotor.