title: Delta-crystallin enhancer binding factor 1 controls the epithelial to mesenchymal transition phenotype and resistance to the epidermal growth factor receptor inhibitor erlotinib in human head and neck squamous cell carcinoma lines.
abstract: OBJECTIVE
  Although the epidermal growth factor receptor (EGFR) is overexpressed in a majority of head and neck squamous cell carcinomas (HNSCC), only a minority of patients derive substantial clinical benefit from EGFR inhibitors. We initiated the present study to identify the mechanisms underlying erlotinib resistance in a panel of HNSCC cell lines.
  
  
  METHODS
  We used [(3)H]thymidine incorporation to characterize the heterogeneity of responsiveness to erlotinib-mediated growth inhibition in a panel of 27 human HNSCC cells. We characterized the molecular mechanisms involved in resistance using a representative subset of six erlotinib-sensitive and erlotinib-resistant HNSCC lines.
  
  
  RESULTS
  Erlotinib had heterogeneous effects on DNA synthesis in HNSCC cells that correlated closely with molecular markers of epithelial to mesenchymal transition (EMT). Specifically, the drug-sensitive lines expressed high levels of E-cadherin and showed limited invasion and migration capabilities. In contrast, the erlotinib-resistant HNSCC lines expressed high levels of the E-cadherin repressor delta-crystallin enhancer binding factor 1 (deltaEF1; Zeb-1) and other mesenchymal markers and low levels of E-cadherin, and they were highly invasive and migratory. Small interfering RNA-mediated knockdown of deltaEF1 in the erlotinib-resistant cell lines (1386LN and UMSCC1) resulted in up-regulation of E-cadherin and increased sensitivity to erlotinib in an E-cadherin-dependent manner.
  
  
  CONCLUSIONS
  DeltaEF1 controls the mesenchymal phenotype and drives erlotinib resistance in HNSCC cells. E-cadherin and deltaEF1 may prove to be useful markers in predicting EGFR inhibitor responsiveness.
authors.affiliation: Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Haddad
authors.forename: Woonyoung
authors.initials: W
authors.lastname: Choi
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
mesh_terms: D015820:Cadherins / Q000096:biosynthesis / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004848:Epithelium / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008648:Mesoderm / Q000378:metabolism*; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000071799:Zinc Finger E-box-Binding Homeobox 1; D038207:delta-Crystallins / Q000737:chemistry*
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D038207:delta-Crystallins; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors