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INTERNATIONAL CONGRESS OF

CancerGenetics

• Impact of Lipid Metabolism Reprogramming on Drug Resistance in Breast Cancer: A Systematic Review

• Negar Sadat Sherafat,¹ Asma Yazdani,² Mohammad Reza Moghaddasnejad,³ Afshin Amari,^4,*
  1. Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran.
  2. Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran.
  3. Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran.
  4. Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
  
  
  
• Introduction: Each year, more than 2.3 million women worldwide are diagnosed with breast cancer (BC), and nearly 700,000 lost their lives to the disease. One of the key characteristics of cancer cells is reprogramming lipid metabolism to create favorable conditions for tumor survival and progression. In this process, lipids undergo alterations in their production, storage mechanisms, and uptake, all of which play significant roles in the growth, diagnosis, and treatment resistance of breast cancer. Tumor cells promote the development and progression of breast cancer by increasing the uptake and synthesis of lipid metabolites such as fatty acids and cholesterol. Moreover, treatment resistance and the failure of chemotherapy in these patients are primarily associated with disruptions in metabolic pathways, particularly elevated lipid production. This study systematically investigates the impact of lipid metabolism reprogramming on treatment resistance in patients with breast cancer.
• Methods: This study was conducted based on the PICO criteria, aligned with the research objective, and following the PRISMA checklist. In this systematic review, a comprehensive search was performed for articles published from 2020 to 2024 across databases including PubMed, SCOPUS, Web of Science, SID, and Magiran, as well as the Google Scholar search engine. Boolean operators and MeSH keywords such as “Breast Cancer,” “Lipid Metabolism,” “Reprogramming,” and “Drug Resistance” were used in the search strategy. Subsequently, two researchers independently screened the retrieved articles according to the inclusion criteria. Finally, after assessing the inclusion and exclusion criteria and critically evaluating the quality of the selected studies, five articles were included in the final review out of an initial 86 articles identified.
• Results: Most studies have demonstrated that the reprogramming of lipid metabolism plays a key role in the development of drug resistance in breast cancer, particularly to agents such as trastuzumab, lapatinib, tamoxifen, and doxorubicin. In trastuzumab-resistant cells with high ERBB2 expression, increased lipid droplet accumulation, enhanced fatty acid synthesis, and alterations in membrane microdomains led to reduced drug-receptor binding and diminished therapeutic efficacy. In lapatinib-resistant cells, the protein CD63 contributed to drug resistance by regulating lipid synthesis and storage, altering membrane composition, and disrupting energy homeostasis. In tamoxifen resistance, cholesterol accumulation in lysosomes and the upregulation of Lamp1/2, along with decreased cathepsin levels, inhibited lysosomal permeability and suppressed apoptotic pathways. The estrogen-related receptor alpha (ERRα) pathway was also implicated in the increased resistance to tamoxifen and doxorubicin. This pathway reprogrammed cellular metabolism by activating glycolysis and oxidative phosphorylation through cholesterol and mevalonate signaling. These changes increased mitochondrial mass and membrane potential, particularly in triple-negative breast cancer cells. In this process, the activation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and ERBB2/HER2 played a crucial role, as they are involved in mitochondrial biogenesis and oxidative metabolism.
• Conclusion: Lipid metabolism reprogramming is recognized as a key mechanism in the development and persistence of drug resistance in breast cancer cells, significantly diminishing the efficacy of targeted therapies by disrupting their signaling pathways. Metabolomic analyses and investigations of metabolic pathways have opened new avenues for identifying effective therapeutic targets. Precise targeting of these pathways—particularly within the tumor microenvironment and its immune components—can lead to the resensitization of resistant cells and enhance the effectiveness of existing treatments. Future research should focus on developing combination and personalized therapies that simultaneously target metabolic pathways and classical drug targets. Thus, leveraging specific metabolic adaptations holds the potential to bring about a significant breakthrough in the management of breast cancer.
• Keywords: Breast Cancer, Lipid Metabolism, Reprogramming, Drug Resistance