Notch receptors in breast cancer: context-dependent roles and therapeutic targeting.
TL;DR
How receptor-specific regulatory mechanisms shape distinct Notch1-4 signaling outputs are discussed and the context-dependent functions and molecular mechanisms of Notch receptors across tumor-cell states, BC molecular subtypes, and tumor microenvironmental components are summarized.
Abstract
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.