title: Epidermal growth factor receptor controls flat dysplastic aberrant crypt foci development and colon cancer progression in the rat azoxymethane model.
abstract: OBJECTIVE
  Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased beta-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic ACF development and cancer progression.
  
  
  METHODS
  Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR.
  
  
  RESULTS
  EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66% to 36% and tumors from 71% to 22% (P < 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the up-regulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-beta, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P < 0.05). Gefitinib also inhibited the activations of extracellular signal-regulated kinase, Src, and AKT pathways in tumors.
  
  
  CONCLUSIONS
  We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis.
authors.affiliation: Department of Medicine, University of Chicago Hospitals and Clinics, Chicago, IL 60637, USA.
authors.forename: Urszula
authors.initials: U
authors.lastname: Dougherty
authors.forename: Amikar
authors.initials: A
authors.lastname: Sehdev
authors.forename: Sonia
authors.initials: S
authors.lastname: Cerda
authors.forename: Reba
authors.initials: R
authors.lastname: Mustafi
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Little
authors.forename: Weihua
authors.initials: W
authors.lastname: Yuan
authors.forename: Sujatha
authors.initials: S
authors.lastname: Jagadeeswaran
authors.forename: Anusara
authors.initials: A
authors.lastname: Chumsangsri
authors.forename: Jorge
authors.initials: J
authors.lastname: Delgado
authors.forename: Maria
authors.initials: M
authors.lastname: Tretiakova
authors.forename: Loren
authors.initials: L
authors.lastname: Joseph
authors.forename: John
authors.initials: J
authors.lastname: Hart
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.forename: Lata
authors.initials: L
authors.lastname: Aluri
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fichera
authors.forename: Marc
authors.initials: M
authors.lastname: Bissonnette
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000517:prevention & control; D056741:Cyclin D; D016213:Cyclins / Q000032:analysis; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077156:Gefitinib; D008297:Male; D011230:Precancerous Conditions / Q000209:etiology* / Q000517:prevention & control; D011799:Quinazolines / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D050796:STAT3 Transcription Factor / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D056741:Cyclin D; D016213:Cyclins; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D018808:Transcription Factor AP-1; D066246:ErbB Receptors; D001397:Azoxymethane; D000077156:Gefitinib