title: c-MYC functions as a molecular switch to alter the response of human mammary epithelial cells to oncostatin M.
abstract: Cytokines play an important role in creating an inflammatory microenvironment, which is now considered a hallmark of cancer. Although tumor cells can exploit cytokine signaling to promote growth, invasion, and metastasis, the response of normal and premalignant epithelial cells to cytokines present in a developing tumor microenvironment remains unclear. Oncostatin M (OSM), an IL-6 family cytokine responsible for STAT3 activation, has been implicated in cancer development, progression, invasion, and metastasis. Paradoxically, OSM can also suppress the growth of normal cells and certain tumor-derived cell lines. Using isogenic human mammary epithelial cells (HMEC) at different stages of neoplastic transformation, we found that OSM signaling suppressed c-MYC expression and engaged a p16- and p53-independent growth arrest that required STAT3 activity. Inhibition of STAT3 activation by expressing a dominant-negative STAT3 protein or a STAT3-shRNA prevented the OSM-mediated arrest. In addition, expression of c-MYC from a constitutive promoter also abrogated the STAT3-mediated arrest, and strikingly, cooperated with OSM to promote anchorage-independent growth (AIG), a property associated with malignant transformation. Cooperative transformation by c-MYC and OSM required PI3K and AKT signaling, showing the importance of multiple signaling pathways downstream of the OSM receptor in defining the cellular response to cytokines. These findings identify c-MYC as an important molecular switch that alters the cellular response to OSM-mediated signaling from tumor suppressive to tumor promoting.
authors: Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors: Charlene E
authors: CE
authors: Kan
authors: Rocky
authors: R
authors: Cipriano
authors: Mark W
authors: MW
authors: Jackson
mesh_terms: D002471:Cell Transformation, Neoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D042361:Mammary Glands, Human / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology; D053683:Oncostatin M / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D015850:Interleukin-6; D009363:Neoplasm Proteins; D053683:Oncostatin M; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; C000614131:CDKN2A protein, human; C489427:MYC protein, human; C508351:OSM protein, human; C494086:STAT3 protein, human; C495901:TP53 protein, human