Lipid metabolism reprogramming: key mechanism of breast cancer endocrine therapy resistance

ER+ (estrogen receptor positive) breast cancer is the most common subtype of breast cancer, for which endocrine therapy is the primary treatment. However, the development of drug resistance severely limits the clinical efficacy. In recent years, lipid metabolism reprogramming, as a key metabolic feature of tumor cells adapting to microenvironmental stress and driving progression and metastasis, has gained increasing attention due to its role in promoting endocrine therapy resistance. This review focuses on the lipid metabolism reprogramming that occurs in ER+ breast cancer cells in response to endocrine therapy, systematically elaborating on the key molecular mechanism changes in fatty acid synthesis, cholesterol metabolism, lipid droplet homeostasis, and mitochondrial fatty acid β-oxidation. These metabolic remodeling processes not only provide survival advantages and energy to drug-resistant cells but also directly promote the formation and development of drug-resistant phenotypes by affecting signal transduction and epigenetic regulation pathways. By integrating the latest research progress in this field, this article aims to deeply reveal the intrinsic connection between lipid metabolism reprogramming and endocrine resistance, providing important theoretical basis and direction for overcoming the bottleneck of drug resistance and developing new combination therapy strategies targeting lipid metabolism.