Expression Patterns of Trefoil Factor 3 and Its Candidate Receptors in St. Gallen Consensus-Defined Breast Cancer Subtypes

Background: Trefoil factor 3 (TFF3) promotes breast cancer (BC) progression through several candidate receptors, including LINGO2, CD147, and CD44. However, their expression patterns and functional relationships across BC subtypes remain unclear. This study aims to investigate the subtype-specific expressions and cooperative functions of TFF3-associated signaling. Methods: TFF3 and candidate receptor expression were analyzed in BC cell lines and patient cohorts from open-source databases. Findings were validated by qPCR, immunoblotting, and immunocytochemistry. siRNA-mediated knockdown and proliferation, colony-formation, and migration assays were used to assess expression regulatory and functional interactions. Results: TFF3 was consistently enriched in ER+ luminal-A/B BC, whereas LINGO2, CD147, and CD44 were preferentially expressed in TNBC. TFF3 expression was inversely associated with its candidate receptors across subtypes. Moreover, TFF3 and LINGO2 formed a negative reciprocal expression regulation and exerted opposing effects on malignant phenotypes. In contrast, TFF3 formed positive reciprocal expression regulation with CD147 and CD44, and their combined depletion enhanced suppression of proliferation, colony formation, and migration. The expression patterns also reflected BC differentiation states, with TFF3 linked to luminal differentiation and CD147/CD44-associated basal-like and stem-like features. Conclusions: The TFF3-associated signaling is rewired across BC subtypes. Its subtype-specific expression and functional interactions provide insight into BC heterogeneity.