Notch receptors in breast cancer: context-dependent roles and therapeutic targeting

Breast cancer (BC) development is influenced by multifactorial mechanisms. Despite significant advancements in early diagnostic techniques and comprehensive therapeutic approaches, BC continues to pose a substantial threat to women's health, exhibiting persistently high incidence and mortality rates. The Notch signaling pathway, a highly conserved evolutionary pathway initially identified in Drosophila, has garnered extensive research interest and is implicated in the pathogenesis of diverse malignancies, including BC. However, accumulating evidence reveals a highly context-dependent role for Notch signaling in cancer, with documented functions ranging from oncogenic to tumor-suppressive depending on the specific cellular and microenvironmental context. Current evidence indicates that Notch1-4 display nonredundant functional divergence in BC. In this review, we discuss how receptor-specific regulatory mechanisms shape distinct Notch1-4 signaling outputs and summarize the context-dependent functions and molecular mechanisms of Notch receptors across tumor-cell states, BC molecular subtypes, and tumor microenvironmental components. We also review current advances and limitations in pan-Notch inhibition and receptor-specific targeting strategies, aiming to provide clearer directions for future Notch receptor-targeted therapy in BC.