Claudin-3 and claudin-4 expression in serous papillary, clear-cell, and endometrioid endometrial cancer.
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.
Konecny
Gottfried E
GE
Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Agarwal
Rachana
R
Keeney
Gary A
GA
Winterhoff
Boris
B
Jones
Monica Brown
MB
Mariani
Andrea
A
Riehle
Darren
D
Neuper
Christina
C
Dowdy
Sean C
SC
Wang
He-Jing
HJ
Morin
Patrice J
PJ
Podratz
Karl C
KC
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
C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; D062465:Claudin-3; D062506:Claudin-4; D008565:Membrane Proteins