Transformation of mammary epithelial cells by 3-phosphoinositide- dependent protein kinase-1 activates beta-catenin and c-Myc, and down-regulates caveolin-1.
3-phosphoinositide-dependent protein kinase-1 (PDK1) plays a pivotal role in coupling growth factor receptor signaling to tumor cell proliferation, survival, and invasion. Protein kinase C (PKC) alpha, but not Akt1, was found previously to be downstream of PDK1-mediated transformation of mammary epithelial cells. To determine the basis for its oncogenic activity, signal transduction pathways mediated by PDK1 in mammary epithelial cells were investigated. beta-Catenin/T-cell factor-dependent promoter activity was markedly activated in PDK1- and PKCalpha-expressing cells, but not in Akt1-expressing cells, which resulted in increased levels of the beta-catenin/T-cell factor target genes c-myc and cyclin D1. In contrast, caveolin-1, of which the transcription is suppressed by c-myc, was down-regulated in PDK1- and PKCalpha-expressing, but not in Akt1-expressing cells. Analysis of 16 breast cancer cell lines established that caveolin-1 expression was either absent or reduced compared with breast epithelial cells, and that PDK1 was elevated in all of the cell lines. Interestingly, all of the cell lines known to be invasive expressed caveolin-1 to some degree, whereas, 5 of 6 cell lines that are not invasive did not express caveolin-1. Therefore, it appears that a concomitant gain of c-myc function and a loss or reduction of caveolin-1 are major determinants of PDK1- and PKCalpha-mediated mammary oncogenesis.
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D003598:Cytoskeletal Proteins; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D051176:beta Catenin; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha