title: Opposing roles of TGF-β and EGF in the regulation of TRAIL-induced apoptosis in human breast epithelial cells.
abstract: Transforming growth factor-beta (TGF-β) induces the epithelial to mesenchymal transition (EMT) in breast epithelial cells and plays an important role in mammary morphogenesis and breast cancer. In non-transformed breast epithelial cells TGF-β antagonizes epidermal growth factor (EGF) action and induces growth inhibition. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to participate in lumen formation during morphogenesis of human breast epithelial cells. Our previous work indicated that sensitivity of human breast epithelial cells to TRAIL can be modulated through the activation of the epidermal growth factor receptor-1 (EGFR). Here, we show that TGF-β opposes EGF-mediated sensitization to TRAIL-induced caspase-8 activation and apoptosis in non-transformed breast epithelial cells. Death-inducing signalling complex (DISC) formation by TRAIL was significantly reduced in cells treated with TGF-β. TGF-β treatment activates cytoprotective autophagy and down-regulates TRAIL-R2 expression at the cell surface by promoting the intracellular accumulation of this receptor. Lastly, we demonstrate that EMT is not involved in the inhibitory effect of TGF-β on apoptosis by TRAIL. Together, the data reveal a fine regulation by EGF and TGF-β of sensitivity of human breast epithelial cells to TRAIL which may be relevant during morphogenesis.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC, Avda Américo Vespucio s/n, 41092 Sevilla, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Cano-González
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC, Avda Américo Vespucio s/n, 41092 Sevilla, Spain. Electronic address: abelardo.lopez@cabimer.es.
authors.forename: Abelardo
authors.initials: A
authors.lastname: López-Rivas
mesh_terms: D015703:Antigens, CD; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D001940:Breast / Q000166:cytology*; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor
keywords: Apoptosis; EGF; Internalization; TGF-β; TRAIL; TRAIL-R2