TGFβ-regulated transcriptional mechanisms in cancer

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Abstract

Transforming growth factor-beta (TGFβ) has been implicated in oncogenesis for many years. The multifunctional activities of TGFβ 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, TGFβ 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 TGFβ owing to genetic alterations or signaling perturbations such as oncogenic Ras signaling. Loss of TGFβ-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 TGFβ on the tumor cells are observed particularly in cells in which TGFβ-signaling remains functional despite loss of growth control by TGFβ. New insights into transcriptional mechanisms activated by TGFβ are providing a better understanding of the cellular changes involved in the switch of TGFβ from a tumor suppressor to a tumor promotor.