title: Raf-1 oncogenic signaling is linked to activation of mesenchymal to             epithelial transition pathway in metastatic breast cancer cells.
abstract: Aberrant activation of the Raf/MEK/MAPK pathway plays a key role in breast             cancer development and progression. Dysregulation of Raf/MEK/MAPK oncogenic signaling             often results from overexpression of the HER-2/Neu tyrosine kinase receptor leading             to chemoendocrine resistance, development of distant metastases and ultimately             poor prognosis in breast cancer patients. HER-2/Neu overexpression is also linked             to activation of the epithelial to mesenchymal transition (EMT) pathway, loss             of adhesion molecules and metastasis. Recently, it has been demonstrated that             cancer cells that undergo EMT acquire a CD44+/CD24-/low basal cancer stem cell-like             phenotype and are characterized by activation of HER-2/Neu and TGFβ oncogenic             signaling pathways with increased capacity of self-renewal, drug resistance, invasion             and distant metastases. Following metastatic dissemination, cancer cells re-activate             certain epithelial properties through mesenchymal to epithelial transition (MET)             to establish neoplastic lesions at secondary sites, although the molecular mechanisms             regulating MET remain elusive. In this study we demonstrate that constitutive             activation of Raf-1 oncogenic signaling induces HER-2/Neu overexpression leading             to the development of distant metastases in ERα+ MCF-7 breast cancer xenografts.             Importantly, development of distant metastases in xenograft models was linked             to activation of the MET pathway characterized by reduced expression of EMT inducer             genes (TGFB2, TWIST1 and FOXC1) and overexpression of BMB7, CXCR7 and EGR family             of transcription factors. In summary, our results demonstrate for the first time             that amplification of Raf/MEK/MAPK oncogenic signaling during tumor growth promotes             the genesis of metastatic lesions from primary tumors by activating the mesenchymal             epithelial transition.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic                     College of Medicine, Rochester, MN, USA.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Leontovich
authors.forename: Shuya
authors.initials: S
authors.lastname: Zhang
authors.forename: Cosima
authors.initials: C
authors.lastname: Quatraro
authors.forename: Ianko
authors.initials: I
authors.lastname: Iankov
authors.forename: Pier Francesco
authors.initials: PF
authors.lastname: Veroux
authors.forename: Mario W
authors.initials: MW
authors.lastname: Gambino
authors.forename: Amy
authors.initials: A
authors.lastname: Degnim
authors.forename: James
authors.initials: J
authors.lastname: McCubrey
authors.forename: James
authors.initials: J
authors.lastname: Ingle
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
authors.forename: Antonino B
authors.initials: AB
authors.lastname: D'Assoro
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020935:MAP Kinase Signaling System; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D047368:Tumor Burden; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D019908:Proto-Oncogene Proteins c-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D051176:beta Catenin; C508053:ERBB2 protein, human