title: An intracellular targeted antibody detects EGFR as an independent prognostic factor in ovarian carcinomas.
abstract: BACKGROUND
  In ovarian cancer, the reported rate of EGFR expression varies between 4-70% depending on assessment method and data on patient outcome are conflicting.
  
  
  METHODS
  In this study we investigated EGFR expression and its prognostic value in a cohort of 121 invasive ovarian carcinomas, using a novel antibody against the intracellular domain of the receptor. We further evaluated an association between EGFR, the nuclear transporter CRM1 as well as COX-2. Furthermore, we evaluated EGFR expression in ten ovarian cancer cell lines and incubated cancer cells with Leptomycin B, a CRM1 specific inhibitor.
  
  
  RESULTS
  We observed a membranous and cytoplasmic EGFR expression in 36.4% and 64% of ovarian carcinomas, respectively. Membranous EGFR was an independent prognostic factor for poor overall survival in ovarian cancer patients (HR 2.7, CI 1.1-6.4, p = 0.02) which was also found in the serous subtype (HR 4.6, CI 1.6-13.4, p = 0.004). We further observed a significant association of EGFR with COX-2 and nuclear CRM1 expression (chi-square test for trends, p = 0.006 and p = 0.013, respectively). In addition, combined membranous EGFR/COX-2 expression was significantly related to unfavorable overall survival (HR 7.2, CI 2.3-22.1, p = 0.001).In cell culture, we observed a suppression of EGFR protein levels after exposure to Leptomycin B in OVCAR-3 and SKOV-3 cells.
  
  
  CONCLUSIONS
  Our results suggest that the EGFR/COX-2/CRM1 interaction might be involved in progression of ovarian cancer and patient prognosis. Hence, it is an interesting anti-cancer target for a combination therapy. Further studies will also be needed to investigate whether EGFR is also predictive for benefit from EGFR targeted therapies.
authors.affiliation: Institute of Pathology, University Hospital Charité Berlin, Germany. aurelia.noske@usz.ch
authors.forename: Aurelia
authors.initials: A
authors.lastname: Noske
authors.forename: Michael
authors.initials: M
authors.lastname: Schwabe
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Buckendahl
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.forename: Elena I
authors.initials: EI
authors.lastname: Braicu
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000912:Antibodies, Neoplasm / Q000276:immunology*; D000918:Antibody Specificity; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000276:immunology; D002277:Carcinoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000032:analysis; D066246:ErbB Receptors / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D053208:Kaplan-Meier Estimate; D028884:Karyopherins / Q000032:analysis / Q000037:antagonists & inhibitors; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D017434:Protein Structure, Tertiary; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000037:antagonists & inhibitors; D016037:Single-Blind Method; D000097606:Exportin 1 Protein
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D014408:Biomarkers, Tumor; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D009363:Neoplasm Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C496540:PTGS2 protein, human; C512478:EGFR protein, human; C038753:leptomycin B