Defining the Tumor-Bone axis: the role of extracellular vesicles in a crucial exchange route for breast cancer development and progression.

Bone disorders frequently manifest as long-term outcomes of breast cancer. Consequently, the relationship between breast cancer and bone metabolism is often studied at advanced stages of the disease. Emerging evidence suggests that bidirectional communication between mammary and bone tissues begins much earlier. In this context, extracellular vesicles (EVs) have been recognized as key mediators of intercellular communication, with emerging evidence supporting their role in breast cancer progression and the regulation of bone metabolism. This review examines bone imbalances occurring throughout the course of breast cancer, the pathophysiological mechanisms behind them, and the role of EVs in their development. From this integrated perspective, we propose the concept of Tumor-Bone Axis, a continuous and dynamic crosstalk between breast cancer and bone cells that supports tumor progression and bone complications. This axis regulates distinct metabolic states governing the activity of breast cancer cells and the balance in bone remodeling, enabling cellular reprogramming events during malignant transformation, immunoediting, tumor growth, and metastasis formation. Additionally, the impact of antineoplastic treatments on this axis may underlie chemoresistance, relapse, or therapy-induced metastasis. While multiple mediators are involved-including cell-to-cell contact, cell migration, osteoimmune interactions, hormones, soluble factors, and nutrients-EVs appear to be critical, especially through their role in exchanging epigenetic regulators of central signaling pathways in these cellular reprogramming events. Understanding the temporal and functional dynamics of the Tumor-Bone Axis and the extracellular vesicular traffic within it could reveal novel diagnostic biomarkers and therapeutic strategies for both breast cancer and its bone-related manifestations.