title: Claudin-3 and claudin-4 expression in serous papillary, clear-cell, and endometrioid endometrial cancer.
abstract: OBJECTIVE
  Tight junction (TJ) proteins claudin-3 and claudin-4 may be differentially expressed in uterine serous papillary carcinoma (USPC), a rare form of endometrial cancer characterized by a particularly poor prognosis. Our aim was to determine the expression pattern and prognostic relevance of claudin-3 and claudin-4 in a large cohort of endometrial cancer patients of diverse histological type and stage.
  
  
  METHODS
  Claudin-3 and claudin-4 expression was studied in a cohort of 287 patients with endometrial cancer including 137 cases of USPC or clear-cell histology using immunohistochemistry. Patients were completely surgically staged. Outcome data is available on all 287 patients.
  
  
  RESULTS
  The rate of claudin-3 and claudin-4 expression was significantly higher in USPC and clear-cell endometrial cancer compared to endometrioid endometrial cancer (claudin-3: 78% and 61% versus 38%, p<.0001; claudin-4: 56% and 44% versus 9%, p<.0001). Furthermore, expression of both TJ proteins was significantly associated with poor clinical outcome (claudin-3, DFS RR 1.70, p=.0087, OS RR 1.62, p=.0247; claudin-4, DFS RR 2.66, p<0.0001, and OS RR 2.50, p<0.0001). However, both markers did not maintain prognostic independence in multivariate analyses, as their expression was tightly associated with more advanced disease stages (p<.0001 for both), and higher nuclear grade (p<.0001 for both).
  
  
  CONCLUSIONS
  These clinical observations confirm the hypothesis based on preclinical evidence that increased expression of claudin-3 and claudin-4 may contribute to the aggressive phenotype of endometrial cancer of serous papillary or clear-cell histology and suggest their potential utility as diagnostic biomarkers and possible targets for therapeutic intervention.
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
authors.forename: Rachana
authors.initials: R
authors.lastname: Agarwal
authors.forename: Gary A
authors.initials: GA
authors.lastname: Keeney
authors.forename: Boris
authors.initials: B
authors.lastname: Winterhoff
authors.forename: Monica Brown
authors.initials: MB
authors.lastname: Jones
authors.forename: Andrea
authors.initials: A
authors.lastname: Mariani
authors.forename: Darren
authors.initials: D
authors.lastname: Riehle
authors.forename: Christina
authors.initials: C
authors.lastname: Neuper
authors.forename: Sean C
authors.initials: SC
authors.lastname: Dowdy
authors.forename: He-Jing
authors.initials: HJ
authors.lastname: Wang
authors.forename: Patrice J
authors.initials: PJ
authors.lastname: Morin
authors.forename: Karl C
authors.initials: KC
authors.lastname: Podratz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D018269:Carcinoma, Endometrioid / Q000378:metabolism* / Q000473:pathology; D062465:Claudin-3; D062506:Claudin-4; D015331:Cohort Studies; D018283:Cystadenocarcinoma, Papillary / Q000378:metabolism* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis
chemical_list: C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; D062465:Claudin-3; D062506:Claudin-4; D008565:Membrane Proteins