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Understanding the initial mechanisms by which epithelial cells transform to an invasive phenotype is critical to the development of diagnostics that can identify the metastatic potential of cancers as well as therapeutic agents that can prevent metastases. Changes in cellular response to the transforming growth factor-beta (TGF-β) cytokine are known to promote epithelial cell invasion and metastasis in part through induction of epithelial-mesenchymal transitions (EMTs). In this report, we demonstrate that non-metastatic human prostate cancer cell lines of increasing Gleason score can be induced to undergo EMT when treated with TGF-β in combination with epidermal growth factor. Mechanistic studies revealed that in cells stably transfected with activated Ras, TGF-β alone induced EMT and that a Ras-Raf-MEK1, but not MEK2, signaling cascade is necessary and sufficient for Erk2 nuclear localization that works in concert with TGF-β to promote EMT. Furthermore, we show for the first time that expression of the transcription factor c-myc, which is phosphorlyated by Erk2, is required for EMT. Characteristically, EMT involved adoption of a spindle-shaped morphology, loss of E-cadherin and increased expression of Vimentin, Fibronectin and Fibroblast Specific Protein-1 (S100A4). Prostate cells undergoing EMT became invasive and expressed several genes associated with metastasis, including MT-MMP1, MMP-2/9, the MMP-9 homodimer, Slug and Twist2. In sum, we demonstrate a novel mechanism by which non-invasive primary prostate tumor cells transition to an invasive phenotype characteristic of malignant tumor cells in response to TGF-β signaling.

carcinogenesis

c-Myc expression and MEK1-induced Erk2 nuclear localization are required for TGF-beta induced epithelial–mesenchymal transition and invasion in prostate cancer