title: Eukaryotic Translation Initiation Factor 4E Is a Feed-Forward Translational Coactivator of Transforming Growth Factor β Early Protransforming Events in Breast Epithelial Cells.
abstract: Eukaryotic translation initiation factor 4E (eIF4E) is overexpressed early in breast cancers in association with disease progression and reduced survival. Much remains to be understood regarding the role of eIF4E in human cancer. We determined, using immortalized human breast epithelial cells, that elevated expression of eIF4E translationally activates the transforming growth factor β (TGF-β) pathway, promoting cell invasion, a loss of cell polarity, increased cell survival, and other hallmarks of early neoplasia. Overexpression of eIF4E is shown to facilitate the selective translation of integrin β1 mRNA, which drives the translationally controlled assembly of a TGF-β receptor signaling complex containing α3β1 integrins, β-catenin, TGF-β receptor I, E-cadherin, and phosphorylated Smad2/3. This receptor complex acutely sensitizes nonmalignant breast epithelial cells to activation by typically substimulatory levels of activated TGF-β. TGF-β can promote cellular differentiation or invasion and transformation. As a translational coactivator of TGF-β, eIF4E confers selective mRNA translation, reprogramming nonmalignant cells to an invasive phenotype by reducing the set point for stimulation by activated TGF-β. Overexpression of eIF4E may be a proinvasive facilitator of TGF-β activity.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Decarlo
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Mestel
authors.affiliation: Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA NYU Cancer Institute, New York University School of Medicine, New York, New York, USA.
authors.forename: Mary-Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, USA Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA NYU Cancer Institute, New York University School of Medicine, New York, New York, USA Robert.schneider@nyumc.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schneider
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D015820:Cadherins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D039201:Integrin alpha3beta1 / Q000096:biosynthesis; D019012:Integrin beta1 / Q000096:biosynthesis / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000235:genetics*; D051899:Smad2 Protein / Q000096:biosynthesis / Q000378:metabolism; D051900:Smad3 Protein / Q000096:biosynthesis / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics*; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D015820:Cadherins; D039561:Eukaryotic Initiation Factor-4E; D039201:Integrin alpha3beta1; D019012:Integrin beta1; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D051176:beta Catenin