p21WAF1/cIP1 mediates the growth response to TGF-β in human epithelial cells

We investigated the mechanism by which cancers evade the growth inhibitory effects of TGF-beta. Using two p21(-/-) somatically deleted human epithelial cell lines, we find that TGF-beta serves as a growth stimulator rather than a growth suppressor to cells lacking p21. In addition, TGF-beta stimulated p21(-/-) cells exhibited a mesenchymal phenotype, demonstrated by an upregulation of vimentin and decreased expression of E-cadherin. Analysis of primary human breast cancers by immunohistochemical labeling confirmed a correlation between p21 loss and positive vimentin expression. These data provide a molecular mechanism explaining how nongastrointestinal cancers can escape the anti-proliferative effects of this cytokine and simultaneously use this pathway for growth advantage.