AGR3 is a non-canonical protein disulfide isomerase family member with dual roles in normal physiology and cancer biology. In healthy tissues, AGR3 is required for calcium-mediated regulation of ciliary beat frequency and mucociliary clearance in airway epithelial cells 1, with expression specifically localized to ciliated cells 2. The protein contains a CXXS active site motif characteristic of non-canonical PDIs, enabling selective protein folding quality control in the secretory pathway 1. In cancer contexts, AGR3 demonstrates complex, cancer-type-dependent functions. In colorectal cancer, AGR3 promotes cancer stemness by activating Wnt/β-catenin signaling and promoting β-catenin nuclear translocation in an FZD4-dependent manner 3. In ovarian cancer, AGR3 expression correlates with improved survival in low-grade and high-grade serous carcinomas 2, yet AGR3 overexpression mediates cisplatin resistance in xenograft models 4. In breast cancer, AGR3 expression patterns are subtype-dependent: elevated AGR3 predicts worse prognosis in luminal subtypes and worse overall survival in low-intermediate grade tumors 5, while reduced expression characterizes basal-like breast cancer 6. Expression correlates positively with epithelial differentiation and inversely with mesenchymal phenotypes across cancer types 7. AGR3 represents a context-dependent biomarker with potential therapeutic significance in specific cancer subtypes.