title: Human Mena+11a isoform serves as a marker of epithelial phenotype and sensitivity to epidermal growth factor receptor inhibition in human pancreatic cancer cell lines.
abstract: OBJECTIVE
  hMena, member of the enabled/vasodilator-stimulated phosphoprotein family, is a cytoskeletal protein that is involved in the regulation of cell motility and adhesion. The aim of this study was to determine whether or not the expression of hMena isoforms correlated with sensitivity to EGFR tyrosine kinase inhibitors and could serve as markers with potential clinical use.
  
  
  METHODS
  Human pancreatic ductal adenocarcinoma cell lines were characterized for in vitro sensitivity to erlotinib, expression of HER family receptors, markers of epithelial to mesenchymal transition, and expression of hMena and its isoform hMena(+11a). The effects of epidermal growth factor (EGF) and erlotinib on hMena expression as well as the effect of hMena knockdown on cell proliferation were also evaluated.
  
  
  RESULTS
  hMena was detected in all of the pancreatic tumor cell lines tested as well as in the majority of the human tumor samples [primary (92%) and metastatic (86%)]. Intriguingly, in vitro hMena(+11a) isoform was specifically associated with an epithelial phenotype, EGFR dependency, and sensitivity to erlotinib. In epithelial BxPC3 cells, epidermal growth factor up-regulated hMena/hMena(+11a) and erlotinib down-regulated expression. hMena knockdown reduced cell proliferation and mitogen-activated protein kinase and AKT activation in BxPC3 cells, and promoted the growth inhibitory effects of erlotinib.
  
  
  CONCLUSIONS
  Collectively, our data indicate that the hMena(+11a) isoform is associated with an epithelial phenotype and identifies EGFR-dependent cell lines that are sensitive to the EGFR inhibitor erlotinib. The availability of anti-hMena(+11a)-specific probes may offer a new tool in pancreatic cancer management if these results can be verified prospectively in cancer patients.
authors.affiliation: Division of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Pino
authors.forename: Michele
authors.initials: M
authors.lastname: Balsamo
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Modugno
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.forename: Massimo
authors.initials: M
authors.lastname: Alessio
authors.forename: Elisa
authors.initials: E
authors.lastname: Melucci
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
authors.forename: Ulrike
authors.initials: U
authors.lastname: Philippar
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Natali
authors.forename: Paola
authors.initials: P
authors.lastname: Nisticò
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000628:therapy*; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004848:Epithelium / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D008840:Microfilament Proteins / Q000737:chemistry* / Q000502:physiology*; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy*; D010641:Phenotype; D011799:Quinazolines / Q000494:pharmacology
chemical_list: C511939:Enah protein, human; D008840:Microfilament Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors