Molecular Mechanisms Underlying Recurrence in Triple-Positive Breast Cancer (ER+/PR+/HER2+) and Potential Repurposing of Multi-Target Inhibitors

Triple-positive breast cancer (TPBC) is characterized by the overexpression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), making its management a therapeutic challenge. Despite the availability of targeted therapies, patients with TPBC often experience recurrence and poor clinical outcomes due to intrinsic and acquired resistance mechanisms. This review summarizes current therapeutic approaches and their limitations, highlights the molecular mechanisms underlying treatment resistance and recurrence, and explores opportunities for drug repurposing, particularly involving multi-target inhibitors. Special emphasis is placed on the interaction between hormone receptor and growth factor receptor pathways, compensatory signaling mechanisms, and predictive biomarkers of recurrence. Furthermore, emerging strategies for drug repurposing using clinically available drugs are analyzed, including in silico, in vitro, and clinical trial evidence, along with their translational implications. Finally, we conclude that drug repurposing and multi-target approaches offer a compelling rationale for the development of novel therapeutic strategies in triple-positive breast cancer. However, their clinical utility remains to be validated through appropriately designed experimental and clinical studies before their impact on recurrence outcomes can be established.