p21 (WAF1/CIP1) Mediates the Growth Response to TGF-b in Human Epithelial Cells

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Abstract
We investigated the mechanism by which cancers evade the growth inhibitory effects of TGF-b. Using two p21-/- somatically deleted human epithelial cell lines, we find that TGF-b serves as a growth stimulator rather than a growth suppressor to cells lacking p21. In addition, TGF-b 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 non-gastrointestinal cancers can escape the anti-proliferative effects of this cytokine and simultaneously use this pathway for growth advantage.

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