title: RhoB determines tumor aggressiveness in a murine EGFRL858R-induced adenocarcinoma model and is a potential prognostic biomarker for Lepidic lung cancer.
abstract: OBJECTIVE
  A crucial event in lung adenocarcinoma progression is the switch from an aerogenous spread toward an infiltrating tumor. Loss of RhoB expression has been suggested to be critical for lung cancer invasion. Here, we tested RhoB expression as a prognostic biomarker in non-small cell lung cancer (NSCLC) with a special focus on lepidic pattern.
  
  
  METHODS
  We analyzed RhoB expression using both IHC and RT-qPCR in two series of operated patients (n = 100 and 48, respectively) and in a series of advanced lepidic adenocarcinoma (n = 31) from different hospitals. Next, we examined the role of RhoB in lung cancer progression in transgenic mice that express inducible EGFR(L858R) crossed with Rhob null mice.
  
  
  RESULTS
  We identified that loss of RhoB expression was strongly associated with worse survival (P = 0.0001) and progression-free survival (P < 0.001) in the first series. We then confirmed these results after multivariate analyses of the second series. In the series of adenocarcinoma with lepidic features issued from a clinical trial (IFCT-0401), we showed that loss of RhoB expression was associated with higher aggressiveness of stage IV. Finally, we showed that EGFR(L858R)/Rhob(+/+) mice developed mainly diffuse lung tumors with a lepidic pattern, whereas EGFR(L858R)/Rhob(+/-) and EGFR(L858R)/Rhob(-/-) developed a greater number of tumors, and aggressive adenocarcinomas with invasive properties.
  
  
  CONCLUSIONS
  We showed that RhoB is not only a strong prognostic factor in NSCLC but it is also critical for the acquisition of an aggressive phenotype of adenocarcinoma.
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France. Université Paul Sabatier, Toulouse, France. Institut Claudius Regaud, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Calvayrac
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France. Université Paul Sabatier, Toulouse, France. Institut Claudius Regaud, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Pradines
authors.affiliation: Université de Toulouse, UPS-INP-ENVT, UMS006, Laboratoire d'histopathologie, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Raymond-Letron
authors.affiliation: Université Paul Sabatier, Toulouse, France. Hôpital Rangueil, Departement d'Anatomo-Cytopathologie, CHU Toulouse, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouquette
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France. Université Paul Sabatier, Toulouse, France. Institut Claudius Regaud, Toulouse, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bousquet
authors.affiliation: Départment d'Epidemiologie, CHU Toulouse, Toulouse, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lauwers-Cances
authors.affiliation: Institut Claudius Regaud, Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.affiliation: Hôpital Tenon, Service de Pneumologie, AP-HP; GRC-UPMC 04 Theranoscan Paris 6 University, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.affiliation: Hôpital de Hautepierre, Pôle de Biologie, Laboratoire de Biochimie et Biologie Moléculaire, CHU Strasbourg, Strasbourg cedex, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Beau-Faller
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France. Université Paul Sabatier, Toulouse, France. Institut Claudius Regaud, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Casanova
authors.affiliation: Université Paul Sabatier, Toulouse, France. Hôpital Larrey, Département de Pneumologie, CHU Toulouse, Toulouse, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Milia
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France. Université Paul Sabatier, Toulouse, France. Institut Claudius Regaud, Toulouse, France. mazieres.j@chu-toulouse.fr favre.gilles@claudiusregaud.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Favre
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France. Université Paul Sabatier, Toulouse, France. Hôpital Larrey, Département de Pneumologie, CHU Toulouse, Toulouse, France. mazieres.j@chu-toulouse.fr favre.gilles@claudiusregaud.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Mazières
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D012307:Risk Factors; D047368:Tumor Burden; D020743:rhoB GTP-Binding Protein / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D020743:rhoB GTP-Binding Protein