title: Nuclear and cytoplasmic accumulation of Ep-ICD is frequently detected in human epithelial cancers.
abstract: BACKGROUND
  We previously demonstrated that nuclear and cytoplasmic accumulation of the intracellular domain (Ep-ICD) of epithelial cell adhesion molecule (EpCAM) accompanied by a reciprocal reduction of its extracellular domain (EpEx), occurs in aggressive thyroid cancers. This study was designed to determine whether similar accumulation of Ep-ICD is a common event in other epithelial cancers.
  
  
  RESULTS
  Ten epithelial cancers were immunohistochemically analyzed using Ep-ICD and EpEx domain-specific antibodies. The subcellular localization of EpEx and Ep-ICD in the human colon adenocarcinoma cell line CX-1 was observed using immunofluorescence. Nuclear and cytoplasmic Ep-ICD expression was increased in cancers of the breast (31 of 38 tissues, 82%), prostate (40 of 49 tissues, 82%), head and neck (37 of 57 tissues, 65%) and esophagus (17 of 46 tissues, 37%) compared to their corresponding normal tissues that showed membrane localization of the protein. Importantly, Ep-ICD was not detected in the nuclei of epithelial cells in most normal tissues. High nuclear and cytoplasmic Ep-ICD accumulation also occurred in the other six epithelial cancer types analyzed - lung, colon, liver, bladder, pancreatic, and ovarian. A concomitant reduction in membrane EpEx expression was observed in a subset of all cancer types. Receiver operating characteristic curve analysis revealed nuclear Ep-ICD distinguished breast cancers with 82% sensitivity and 100% specificity and prostate cancers with 82% sensitivity and 78% specificity. Similar findings were observed for cytoplasmic accumulation of Ep-ICD in these cancers. We provide clinical evidence of increased nuclear and cytoplasmic Ep-ICD accumulation and a reduction in membranous EpEx in these cancers.
  
  
  CONCLUSIONS
  Increased nuclear and cytoplasmic Ep-ICD was observed in all epithelial cancers analyzed and distinguished them from normal tissues with high-sensitivity, specificity, and AUC. Development of a robust high throughput assay for Ep-ICD will facilitate the determination of its diagnostic, prognostic and therapeutic relevance in epithelial cancers.
authors.affiliation: Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Department of Otolaryngology-Head and Neck Surgery Program, Mount Sinai Hospital, University of Toronto Medical School, Department of Otolaryngology-Head and Neck Surgery, Toronto, Ontario, Canada. rralhan@mtsinai.on.ca
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
authors.forename: Helen C-H
authors.initials: HC
authors.lastname: He
authors.forename: Anthony K-C
authors.initials: AK
authors.lastname: So
authors.forename: Satyendra C
authors.initials: SC
authors.lastname: Tripathi
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.forename: Md Raghibul
authors.initials: MR
authors.lastname: Hasan
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kashat
authors.forename: Christina
authors.initials: C
authors.lastname: MacMillan
authors.forename: Shyam Singh
authors.initials: SS
authors.lastname: Chauhan
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Freeman
authors.forename: Paul G
authors.initials: PG
authors.lastname: Walfish
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D012372:ROC Curve
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule