The double-edged nature of β-catenin: from multicellular innovation to cancer vulnerability

β-Catenin embodies a fundamental paradox of multicellular life. The same molecular system that enabled the emergence of animal multicellularity by coupling cell-cell adhesion to gene regulation also creates a vulnerability that can drive cancer when misregulated. As a central regulator of cell physiology, β-catenin integrates cell-cell adhesion, mechanotransduction, and gene expression to coordinate tissue architecture with transcriptional programs controlling proliferation, differentiation, and homeostasis. Phylogenomic analyses indicate that bona fide β-catenins form a metazoan-specific monophyletic clade derived from an ancestral armadillo-repeat scaffold. This conserved superhelical structure generates a single interaction groove that mediates mutually exclusive binding to E-cadherin, adenomatous polyposis coli (APC), and T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors. Although this architecture enabled early metazoans to coordinate adhesion, signaling, and morphogenesis, it also introduced an intrinsic regulatory vulnerability. Mutations that disrupt β-catenin degradation stabilize the protein, uncoupling Wnt signaling from its normal regulatory constraints and driving persistent proliferative transcriptional programs. In parallel, emerging structural and biophysical studies reveal conformational plasticity and mechanosensitive properties that enable dynamic partitioning between adhesive and signaling pools. Disruption of these regulatory layers promotes tumor progression, metastasis, immune evasion, and therapy resistance, positioning β-catenin as both a central oncogenic node and a challenging therapeutic target. In this review, we integrate evolutionary, structural, and mechanobiological perspectives to illustrate how β-catenin exemplifies the double-edged nature of biological innovation, an ancient protein that enabled multicellular organization yet whose dysregulation underlies fundamental mechanisms of human cancer.