High-level cytoplasmic claudin 3 expression is an independent predictor of poor survival in triple-negative breast cancer

Abstract

Background: The subtype of claudin-low breast cancer can be reliably determined only by gene-expression profiling. Attempts have been made to develop immunohistochemical surrogates, which nearly always focus on membranous claudin expression. Methods: We assessed the immunohistochemical expression of both membranous and cytoplasmic claudins 3, 4 and 7 in a series of 197 non-metastatic breast cancers, enriched with triple-negative breast cancers (TNBCs; 60%). The expression of epithelial-to-mesenchymal transition-regulating transcription factors Sip1, Zeb1 and vimentin had previously been determined in the same material. Results: In multivariate analysis, strong cytoplasmic claudin 3 expression was associated with poor relapse-free survival (RFS), disease-free survival, distant disease-free survival, breast cancer-specific survival and overall survival among TNBC patients (for RFS, RR 5.202, 95% CI 1.210-22.369, p=0.027, vs. T-class, RR 0.663, 95% CI 0.168-2.623, p=0.558, and N-class, RR 3.940, 95% CI 0.933-16.631, p=0.062). Cytoplasmic claudin 3 expression was also associated with strong nuclear Sip1 expression (p=0.000053), TNBC phenotype (p=0.012) and within them, non-basal-like phenotype (p=0.026). Cytoplasmic claudin 7 was associated with dismal RFS (RR 6.328, 95% CI 1.401-28.593, p=0.016, vs. T-class, RR 0.692, 95% CI 0.242-1.982, p=0.493, and N-class, RR 2.981, 95% CI 1.1016-8.749, p=0.047). Low cytoplasmic expression of claudins 3, 4 and 7 together also predicted poor RFS (RR 6.070, 95% CI 1.347-27.363, p=0.019, vs. T-class, RR 0.677, 95% CI 0.237-1.934, p=0.467, and N-class, RR 3.167, 95% CI 1.079-9.290, p=0.036). Conclusions: Immunohistochemical expression levels of cytoplasmic claudins 3 and 7 appear to be novel prognostic factors in TNBC.