title: Constitutive activation of signal transducer and activator of transcription 5 contributes to tumor growth, epithelial-mesenchymal transition, and resistance to epidermal growth factor receptor targeting.
abstract: OBJECTIVE
  Signal transducer and activator of transcription 5 (STAT5) is activated in squamous cell carcinoma of the head and neck (SCCHN), where targeting of STAT5 inhibits tumor growth in vitro and in vivo. The role of STAT5 activation in carcinogenesis, tumor progression, and response to therapy remains incompletely understood. In this study, we investigated the effects of STAT5 activation on squamous epithelial carcinogenesis and response to therapy.
  
  
  METHODS
  The functional consequences of STAT5 activation in squamous epithelial carcinogenesis were examined using cells derived from normal (Het-1A) and transformed mucosal epithelial cells engineered to express constitutive-active mutants of STAT5.
  
  
  RESULTS
  The growth rate of stable clones derived from both normal and transformed squamous epithelial cells expressing the constitutive-active STAT5 was increased. In SCCHN xenografts, tumor volumes were increased in constitutive-active STAT5 mutant cells compared with vector-transfected controls. Constitutive activation of STAT5 significantly increased cell migration and invasion through Matrigel, as well as the transforming efficiency of SCCHN cells in vitro, as assessed by soft agar assays. The constitutive-active STAT5 clones derived from SCCHN cells showed changes consistent with an epithelial-mesenchymal transition including decreased expression of E-cadherin and increased vimentin in comparison with control transfectants. In these cells, STAT5 activation was associated with resistance to cisplatin-mediated apoptosis and growth inhibition induced by the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib.
  
  
  CONCLUSIONS
  These results suggest that constitutive STAT5 signaling enhances tumor growth, invasion, and epithelial-to-mesenchymal transition in squamous epithelial carcinogenesis and may contribute to resistance to epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Koppikar
authors.forename: Vivian Wai Yan
authors.initials: VW
authors.lastname: Lui
authors.forename: David
authors.initials: D
authors.lastname: Man
authors.forename: Sichuan
authors.initials: S
authors.lastname: Xi
authors.forename: Raymond Liu
authors.initials: RL
authors.lastname: Chai
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nelson
authors.forename: Allison B J
authors.initials: AB
authors.lastname: Tobey
authors.forename: Jennifer Rubin
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009857:Oncogenes; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D066246:ErbB Receptors