FAT2 inhibits breast cancer cell migration, invasion, and epithelial–mesenchymal transition through transcriptional upregulation of CLDN19

Background: FAT atypical cadherin 2 (FAT2), a member of the protocadherin superfamily involved in cell adhesion and polarity, remains incompletely characterized in breast cancer. This study aimed to elucidate the expression pattern, clinical significance, and functional mechanisms of FAT2 in breast cancer. Methods: findings. Results: FAT2 mRNA was significantly downregulated in breast cancer tissues and was associated with advanced clinical stage, higher T stage, and negative hormone receptor status. High FAT2 expression correlated with longer overall survival, particularly in the ER-positive subgroup. Functionally, recombinant FAT2 protein inhibited cell migration and invasion at sub-cytotoxic concentrations and reversed the EMT phenotype. Integrative bioinformatics analysis identified the tight junction protein CLDN19 as a key downstream effector of FAT2, and rescue experiments demonstrated that CLDN19 knockdown markedly attenuated FAT2-mediated anti-migratory and anti-EMT effects. Immunohistochemical analysis validated the concurrent downregulation and strong positive correlation of FAT2 and CLDN19 in clinical specimens. Conclusions: FAT2 functions as a tumor suppressor in breast cancer by inhibiting migration, invasion, and EMT through transcriptional upregulation of CLDN19. The FAT2-CLDN19 axis represents a potential prognostic biomarker and therapeutic target for anti-metastatic intervention in breast cancer.