Targeting mitochondrial metabolism to overcome hormone resistance in breast cancer

Breast cancer remains a leading cause of cancer-related morbidity in women worldwide, with hormone receptor-positive (HR +) subtypes comprising approximately 70% of cases. Despite advances in endocrine therapies, the development of hormone resistance poses a major challenge, often leading to treatment failure and disease progression. This review addresses the central problem of resistance in HR + breast cancer (HR + BC), focusing on key mechanisms such as mutations in the estrogen receptor (ER), activation of alternative survival pathways including the PI3K/Akt/mTOR axis, and the inherent heterogeneity of tumors. Emerging therapies aim to overcome these barriers by combining hormone treatments with targeted inhibitors. Special emphasis is placed on novel approaches involving mitochondrial disruption, epigenetic modulation, and manipulation of the tumor microenvironment. These strategies reflect a shift toward personalized medicine, where molecular profiling and biomarker identification guide individualized treatment plans. Understanding and targeting the multifactorial nature of resistance in HR + BC is essential to improving therapeutic outcomes. A multidisciplinary, mechanism-based approach offers the most promise for restoring treatment sensitivity and enhancing long-term survival.