Context-dependent Regulation of Epithelial Plasticity and Lineage Identity by the p53 Family in Cancer

The p53 family of transcription factors-comprising p53, p63, and p73-is traditionally recognized for its critical roles in tumor suppression, genomic stability, and epithelial development.While p53 is primarily characterized as a stress-responsive regulator, p63 and p73 possess distinct functions in lineage specification and differentiation.Recent studies have expanded this paradigm, revealing that the p53 family exerts pivotal, context-dependent roles in regulating epithelial plasticity, a process central to tumor progression, heterogeneity, and therapeutic resistance.In this review, we summarize recent advances in understanding the integrated roles of p53, p63, and p73 in governing epithelial plasticity and lineage identity.We emphasize isoform-specific functions, highlighting ΔNp63 as a master regulator of epithelial identity through enhancer-mediated transcriptional programs.In contrast, p53 and p73 act as dynamic modulators of plasticity by responding to oncogenic stress and microenvironmental cues that influence the epithelial-mesenchymal transition, hybrid cell states, and adaptive responses.We further discuss how mutant p53 promotes plasticity, stemness, and invasion through the rewiring of transcriptional and signaling networks, often in cooperation with the TGF-β, Wnt/β-catenin, and Hippo-YAP/TAZ pathways.Collectively, the p53 family represents a central regulatory axis linking epithelial lineage stability to phenotypic plasticity in cancer.