title: Growth factor signaling induces metastasis genes in transformed cells: molecular connection between Akt kinase and osteopontin in breast cancer.
abstract: Malignant tumors are characterized by excessive growth, immortalization, and metastatic spread, whereas benign tumors do not express gene products that mediate invasion. The molecular basis for this difference is incompletely understood. We have screened signal transduction molecules associated with the epidermal growth factor (EGF) receptor and have identified constitutive phosphorylation, indicative of activation, of Akt kinase in MT2994 breast cancer cells. In contrast, cells of the benign breast epithelial cell lines Comma-D and FSK-7 are immortalized through pathways that are independent of the EGF-phosphatidylinositol 3-kinase-Akt kinase cascade, but this is not associated with invasiveness. Transfection of constitutively active Akt kinase causes accelerated cell division and osteopontin expression. Conversely, dominant-negative Akt kinase slows cell cycle progression and suppresses osteopontin expression. The manipulation of osteopontin expression in this setting by transfection of the gene or its antisense does not affect the growth rate of the cells but alters cell motility and anchorage independence. Therefore, Akt kinase activates two distinct genetic programs: the program of growth and survival, which is independent of osteopontin expression, and the program of invasiveness and anchorage independence, which is mediated by osteopontin. These studies define Akt kinase as a molecular bridge between cell cycle progression and dissemination.
authors.affiliation: Department of Radiation Oncology, New England Medical Center, Tufts University School of Medicine, 750 Washington Street, Boston, MA 02111, USA.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Georg F
authors.initials: GF
authors.lastname: Weber
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D053495:Osteopontin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D053495:Osteopontin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse