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Loss of Phosphatase and Tensin Homologue Increases Transforming Growth Factor ß–Mediated Invasion with Enhanced SMAD3 Transcriptional Activity

Departments of ¹ Surgery, ² Pharmacology and Cancer Biology, ³ Pathology, ⁴ Medicine, and ⁵ Neurobiology, Duke University Medical Center, Durham, North Carolina

Requests for reprints: Jeremy N. Rich, Division of Neurology, Duke University Medical Center, Box 2900, Durham, NC 27710. Phone: 919-681-1693; Fax: 919-684-6514; E-mail: rich0001{at}mc.duke.edu.

In normal epithelial tissues, the multifunctional cytokine transforming growth factor-ß (TGF-ß) acts as a tumor suppressor through growth inhibition and induction of differentiation whereas in advanced cancers, TGF-ß promotes tumor progression through induction of tumor invasion, neoangiogenesis, and immunosuppression. The molecular mechanisms through which TGF-ß shifts from a tumor suppressor to a tumor enhancer are poorly understood. We now show a role for the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in repressing the protumorigenic effects of TGF-ß. The TGF-ß effector SMAD3 inducibly interacts with PTEN on TGF-ß treatment under endogenous conditions. RNA interference (RNAi) suppression of PTEN expression enhances SMAD3 transcriptional activity and TGF-ß–mediated induction of SMAD3 target genes whereas reconstitution of PTEN in a null cancer cell line represses the expression of TGF-ß–regulated target genes. Targeting PTEN expression through RNAi in a PTEN wild-type cell line increases TGF-ß–mediated invasion but does not affect TGF-ß–mediated growth inhibition. Reconstitution of PTEN expression in a PTEN-null cell line blocks TGF-ß–induced invasion but does not modulate TGF-ß–mediated growth regulation. These effects are distinct from Akt and Forkhead family members that also interact with SMAD3 to regulate apoptosis or proliferation, respectively. Pharmacologic inhibitors targeting TGF-ß receptors and phosphatidylinositol 3-kinase signaling downstream from PTEN cooperate to block TGF-ß–mediated invasion. Thus, the loss of PTEN expression in human cancers may contribute to a role for TGF-ß as a tumor enhancer with specific effects on cellular motility and invasion. (Cancer Res 2005; 65(24): 11276-81)

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