A CLDN1-negative phenotype predicts poor prognosis in triple-negative breast cancer.
BACKGROUND
Triple-negative breast cancer (TNBC) is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs) presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs.


METHODS
The surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed.


RESULTS
Positive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014). The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003). Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS) in both lymph node positive (LN+) and negative (LN-) cases (both P<0.001). Similarly it was also associated with shorter overall survival (OS)(P = 0.003 in LN+ cases; P = 0.018 in LN- cases). In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008). Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P = 0.002). However, neither CLDN4 nor CLDN7 expression was associated with survival.


CONCLUSIONS
In TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor in this heterogeneous subtype of breast cancer.
Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Fei
F
Ma
Department of Medical Oncology, Beijing DiTan Hospital, Capital Medical University, Beijing, China.
Xiaoyan
X
Ding
Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Ying
Y
Fan
Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Jianming
J
Ying
Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Shan
S
Zheng
Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Ning
N
Lu
Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Binghe
B
Xu
D000328:Adult; D044584:Carcinoma, Ductal / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018275:Carcinoma, Lobular / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D062445:Claudin-1 / Q000235:genetics* / Q000378:metabolism; D062506:Claudin-4 / Q000235:genetics / Q000378:metabolism; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D008875:Middle Aged; D060787:Neoplasm Grading; D010641:Phenotype; D011379:Prognosis; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology
C568108:CLDN1 protein, human; C491875:CLDN2 protein, human; C568157:CLDN4 protein, human; C473255:CLDN7 protein, human; D062445:Claudin-1; D062506:Claudin-4; D057167:Claudins