Wnt ligands in breast cancer metastasis: unraveling their dual roles and therapeutic potential.

Breast cancer metastasis represents not only the most advanced stage of the disease but also the leading cause of breast cancer-related mortality. Despite notable advances in early detection and primary treatment, the emergence of metastasis frequently leads to therapeutic failure and poor survival outcomes. Metastasis is driven by complex molecular alterations and dynamic interactions between tumor cells and the surrounding microenvironment. Among the regulatory pathways implicated, Wnt signaling plays a central role in orchestrating metastatic progression. Notably, Wnt ligands demonstrate context-dependent and dual functionality. They may promote metastasis by enhancing epithelial-mesenchymal transition (EMT), stemness, and cellular motility, or conversely, act to preserve tissue homeostasis and restrain invasion depending on tumor subtype, microenvironmental cues, and downstream signaling networks. This review provides a comprehensive overview of the context-dependent roles of Wnt ligands in breast cancer metastasis, highlighting their impact on EMT, stemness, immune evasion, and organ-specific colonization. We also discuss recent advances in therapeutically targeting Wnt signaling, along with the challenges and opportunities in clinical translation. Understanding the complex and dual-function signaling mediated by Wnt ligands can be helpful for the development of precision medicine strategies aimed at improving outcomes in breast cancer patients.