CDH3 in human tumors: tumor biology and potential therapeutic target

Cadherin-3 (CDH3), which encodes P-cadherin, is a classical cadherin involved in epithelial architecture, basal-cell identity, and tissue repair. Once viewed primarily as a structural adhesion molecule, CDH3 is now recognized as a context-dependent regulator of tumor progression and a candidate therapeutic target across several human malignancies. Available evidence indicates that CDH3 is frequently overexpressed in breast, lung, gastric, colorectal, pancreatic, biliary, ovarian, and glioblastoma settings, where it is commonly linked to high grade, invasion, metastasis, therapy resistance, and unfavorable outcomes. A unidirectional interpretation is nevertheless insufficient. In melanoma, bladder carcinoma, hepatocellular carcinoma, renal cancer, and selected lineage-specific settings, CDH3 loss, cytoplasmic redistribution, or restoration can instead associate with altered adhesion control, reduced invasion, or bidirectional phenotypes. Mechanistically, CDH3 operates at the intersection of cell-cell adhesion and signaling output. Its dysregulation is shaped by promoter methylation, chromatin remodeling, transcription-factor programs, noncoding RNAs, oxidative stress, and protein-stability pathways. Functionally, CDH3 can amplify epidermal growth factor receptor and insulin-like growth factor 1 receptor signaling, cooperate with Wnt and Rho GTPase circuits, organize collective migration and extracellular-matrix remodeling, support stem-like and metabolic states, and integrate hypoxia- or exosome-driven communication. Translationally, CDH3 has progressed from a tumor-associated antigen to a platform for monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engagers, radioimmunotherapy, and apoptosis-inducing bispecific constructs. Clinical implementation remains constrained by expression heterogeneity, normal-tissue expression, and the lack of robust companion diagnostics. Clarifying its lineage dependence, membrane-functional state, and biomarker-guided therapeutic window will be essential for converting promising biological knowledge into clinically useful diagnostics and treatments.