Hippo pathway at the crossroads of stemness and therapeutic resistance in breast cancer

Breast cancer, the most frequently diagnosed cancer in women globally, is a heterogeneous disease with distinct subtypes requiring distinct therapeutic approaches. Regardless of molecular subtyping, breast cancer stem cells significantly contribute to tumor heterogeneity, distant dissemination, and therapeutic resistance. The Hippo pathway is a key regulator of organogenesis and tissue development, and its deregulation is common in breast cancer and linked to cancer stem cell features across several cancer types. Dysfunctional pathway activity leads to the aberrant activation of Hippo downstream effectors, the Yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ), which promote epithelial-to-mesenchymal transition, growth factor-independent proliferation, and maintenance of the breast cancer stem cells' niche. This review summarizes the regulation of the Hippo pathway, emphasizing its significant role in coordinating stemness-related mechanisms in breast cancer. An overview of how the Hippo pathway fuels stemness in triple-negative breast cancer, the most aggressive BC subtype, is then provided. We also discuss how the activation of stem cell-like properties, driven by dysregulation of the Hippo pathway, contributes to the development of resistance to current therapies across the spectrum of breast cancer subtypes.