Breast cancer is the leading cause of cancer death in women. At present, chemotherapy is the main method to treat breast cancer in addition to surgery and radiotherapy, but the process of chemotherapy is often accompanied by the development of drug resistance, which leads to a reduction in drug efficacy. Furthermore, mounting evidence indicates that drug resistance is caused by dysregulated cellular metabolism, and metabolic reprogramming, including enhanced glucose metabolism, fatty acid synthesis and glutamine metabolic rates, is one of the hallmarks of cancer. Changes in metabolism have been considered one of the most important causes of resistance to treatment, and knowledge of the mechanisms involved will help in identifying potential treatment deficiencies. To improve women’s survival outcomes, it is vital to elucidate the relationship between metabolic reprogramming and drug resistance in breast cancer. This review analyzes and investigates the reprogramming of metabolism and resistance to breast cancer therapy, and the results offer promise for novel targeted and cell-based therapies.
Therapeutic targeting of tumor vulnerabilities is emerging as a key area of research. This review is focused on exploiting the vulnerabilities of tumor cells and the immune cells in the tumor immune microenvironment (TIME), including tumor hypoxia, tumor acidity, the bidirectional proton-coupled monocarboxylate transporters (MCTs) of lactate, mitochondrial oxidative phosphorylation (OXPHOS), and redox enzymes in the tricarboxylic acid cycle. Cancer cells use glucose for energy even under normoxic conditions. Although cancer cells predominantly rely on glycolysis, many have fully functional mitochondria, suggesting that mitochondria are a vulnerable target organelle in cancer cells. Thus, one key distinction between cancer and normal cell metabolism is metabolic reprogramming. Mitochondria-targeted small molecule inhibitors of OXPHOS inhibit tumor proliferation and growth. Another hallmark of cancer is extracellular acidification due lactate accumulation. Emerging results show that lactate acts as a fuel for mitochondrial metabolism and supports tumor proliferation and growth. Metabolic reprogramming occurs in glycolysis-deficient tumor phenotypes and in kinase-targeted, drug-resistant cancers overexpressing OXPHOS genes. Glycolytic cancer cells located away from the vasculature overexpress MCT4 transporter to prevent overacidification by exporting lactate, and the oxidative cancer cells located near the vasculature express MCT1 transporter to provide energy through incorporation of lactate into the tricarboxylic acid cycle. MCTs are, therefore, a vulnerable target in cancer metabolism. MCT inhibitors exert synthetic lethality in combination with metformin, a weak inhibitor of OXPHOS, in cancer cells. Simultaneously targeting multiple vulnerabilities within mitochondria shows synergistic antiproliferative and antitumor effects. Developing tumor-selective, small molecule inhibitors of OXPHOS with a high therapeutic index is critical to fully exploiting the mitochondrial vulnerabilities. We and others developed small-molecule inhibitors containing triphenylphosphonium cation that potently inhibit OXPHOS in tumor cells and tissues. Factors affecting tumor cell vulnerabilities also impact immune cells in the TIME. Glycolytic tumor cells supply lactate to the tumor-suppressing regulatory T cells overexpressing MCTs. Therapeutic opportunities for targeting vulnerabilities in tumor cells and the TIME, as well as the implications on cancer health disparities and cancer treatment, are addressed.
Breast cancer is characterized by considerable metabolic diversity. A relatively high percentage of patients diagnosed with breast carcinoma do not respond to standard-of-care treatment, and alteration in metabolic pathways nowadays is considered one of the major mechanisms responsible for therapeutic resistance. Consequently, there is an emerging need to understand how metabolism shapes therapy response, therapy resistance and not ultimately to analyze the metabolic changes occurring after different treatment regimens. The most commonly applied neoadjuvant chemotherapy regimens in breast cancer contain an anthracycline (doxorubicin or epirubicin) in combination or sequentially administered with taxanes (paclitaxel or docetaxel). Despite several efforts, drug resistance is still frequent in many types of breast cancer, decreasing patients’ survival. Understanding how tumor cells rapidly rewire their signaling pathways to persist after neoadjuvant cancer treatment have to be analyzed in detail and in a more complex system to enable scientists to design novel treatment strategies that target different aspects of tumor cells and tumor resistance. Tumor heterogeneity, the rapidly changing environmental context, differences in nutrient use among different cell types, the cooperative or competitive relationships between cells pose additional challenges in profound analyzes of metabolic changes in different breast carcinoma subtypes and treatment protocols. Delineating the contribution of metabolic pathways to tumor differentiation, progression, and resistance to different drugs is also the focus of research. The present review discusses the changes in glucose and fatty acid pathways associated with the most frequently applied chemotherapeutic drugs in breast cancer, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies.
Frontiers in Bioengineering and Biotechnology
Synthetic Biology and Metabolomics: Novel Insight in Oncology Research