Polymorphisms in CLDN1 are associated with age and differentiation of triple-negative breast cancer patients

Hu, Aimin; Li, Junyu; Ruan, Shufang; Fan, Ying; Liao, Yuqian

The principle functions of TJs include preventing the mixing of membrane proteins between the apical and basolateral membranes; and controlling the paracellular passage of ions and solutes in between cells [20] . TJs play important roles in tumor progression and metastasis [21] . A disruption of TJs during tumorigenesis generally leads to invasiveness, loss of cohesion, and lack of differentiation in cancer cells [21] . CLDNs are the first components identified to be involved in sealing in TJs [22] . To date, 27 CLDN family members have been identified; each CLDN has a different tissue-expression pattern and function [22, 23] . Thus, CLDNs may serve both as biomarkers in detecting cancer and as possible targets in cancer therapeutics [24] . CLDN1 is one of the most commonly investigated CLDNs, but the association between polymorphisms in CLDN1 and TNBC has never been reported. CLDN1 is a 17 kb gene that codes for a 3.4 kb transcript which translates to an important protein CLDN1 [25] . It has been reported that polymorphisms in CLDN1 are associated with the risk of cancer [14] , small vessel vascular dementia [26] , leukoaraiosis [27] , and hepatitis C virus infection [28, 29] . In Hahn-Strömberg V's study, they found that CLDN1 rs9869263 genotype was related to risk of colon cancer and polymorphisms in CLDN7 were associated with differentiation and age of colon cancer [14] . Chen et al. reported that CLDN1 rs17501976 polymorphism was significantly associated with a decreased susceptibility to colorectal cancer in a Chinese population [30] . Polymorphisms investigated in our study have never been reported in cancer patients. We first demonstrated that rs10513846 and rs9283658 genotypes were significantly associated with age and grade in TNBC patients. As age and differentiation have been proved to be prognostic factors for breast cancer [31, 32] , our results indicate the potential role of polymorphisms in CLDN1 as biomarkers for tumor invasion or prognosis. Though researches about polymorphisms in CLDN1 are rare, protein CLDN1 has been widely investigated in cancers. CLDN1 can promote or suppress tumor proliferation in different cancers or even in different histological subtypes of the same cancer. The over expression of CLDN1 has been reported to increase cell invasion in colorectal cancer [33] and oral squamous cell carcinoma (OSCC) [34] . CLDN1 has long been considered as a tumor suppressor in breast cancer. But recently, some studies showed that the expression level of CLDN1 was low in luminal-like and claudin-low breast cancers, while the expression level of CLDN1 was high in basal-like, most ER negative, BRCA1, medullary breast cancers [35] . Whether CLDN1 plays tumor-facilitating role in basal-like breast cancer or TNBC still needs to be proved.