Transforming growth factor-beta and breast cancer: Tumor promoting effects of transforming growth factor-β

Although the transforming growth factor (TGF)-βs can be tumor suppressive [1], there is increasing evidence that TGF-β secretion by tumor cells and/or stromal cells within the peritumoral microenvironment can contribute to tumor maintenance and progression. How, then, can TGF-βs be both tumor suppressive and tumor promoting? This apparent paradox is reconciled by a study showing that, in a mouse skin model of chemical carcinogenesis, targeted expression of TGF-β1 in suprabasal keratinocytes appears to have dual effects. It suppresses the formation of benign skin tumors, but once tumors develop, it enhances their progression to a highly invasive spindle cell phenotype [2**]. These results suggest that the effects of TGF-β1 are biphasic: TGF-β1 acts early as a tumor suppressor, probably by inhibiting the proliferation of nontransformed cells, and it acts later as a tumor promoter by eliciting an epithelial-to-mesenchymal transition (EMT). Additional experiments have suggested that upregulation of TGF-β3 in the spindle carcinomas was responsible for maintenance of this invasive phenotype [2**]. This is consistent with TGF-β3 expression at sites in mouse embryos where epithelial-mesenchymal interactions are important, like the lung and palatal shelves [3,4], and also the abnormal lung development and cleft palate observed in TGF-β3 null mice [5]. Also consistent with an early tumor suppressive effect is the recent observation that tgf-β1-/-mice develop an accelerated progression of epithelial hyperplasia to colonic adenomas and cancers [6*]. The existence of dual effects for TGF-βs in tumor progression follows the observation that TGF-β-induced growth inhibitory responses and extracellular matrix responses may represent distinct processes in certain cell types. For example, overexpression of the antagonistic Smad, Smad7, in pancreatic carcinoma cell lines not only suppresses TGF-β1-mediated growth inhibition, but enhances the ability of TGF-β1 to induce matrix associate