Relationship between metabolic reprogramming and drug resistance in breast cancer

Abstract

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.

Keywords: Breast cancer; drug resistance; fatty acid synthesis; glucose metabolism; metabolic reprogramming.

Figure 1

Metabolic pathway in breast cancer cells. Reprogramming of the metabolism, including glucose metabolism, fatty acid synthesis, and amino acid metabolism. TCA, tricarboxylic acid cycle; G-6-P, glucose-6-phosphate; F6P, fructose-6-phosphate; F1,6P, fructose-1,6-bisphosphate; G-3-P, glyceraldehyde 3 phosphate; DHAP, dihydroxyacetone phosphate; 1,3-BPG, 1,3-bisphosphoglycerate, 3-PG, 3-phosphoglycerate; 2-PG, 2-phosphoglycerate; PEP, phosphoenolpyruvate; OAA, oxaloacetate; α-KG, α-ketoglutarate; GLUT, glucose transporter; HK, hexokinase; PKM2, pyruvate kinase isozyme type 2; LDHA, lactate dehydrogenase A; MCT1, monocarboxylate transporter 1; PDK, pyruvate dehydrogenase kinase; PDH, pyruvate dehydrogenase; acetyl-CoA carboxylase; FASN, fatty acid synthase; CPT1, carnitine palmitoyl transferase 1; 3PG, 3-phospho-glycerate; GSH, reduced glutathione; GLU, glutamate; GLUT, glucose transporter; PHGDH, phosphoglycerate dehydrogenase; PSAT1, phosphoserine aminotransferase 1; SLC1A5, solute carrier family 1 member 5; GLS, glutaminase; PSPH, 1-3-phosphoserine phosphatase; BCAAs, branched-chain amino acids; BCAT1, branched-chain amino acid transaminase 1; BCAT2, branched-chain amino acid transaminase 2; BCKA, branched-chain a-keto acid; MCD, malonyl-CoA decarboxylase; ACC, Acetyl-CoA carboxylase; MCT Monocarboxylate transporter.

Figure 2

Important role of mTOR related pathway in metabolic reorganization of breast cancer. PI3K and Ras regulate Akt and ERK, which in turn induce changes in intermediate metabolism to promote anabolic processes. Potential Notch signaling crosstalk with other pathways in breast cancer. In addition, they also induce the activation of mTORC1, thus further supporting the rewiring of cellular metabolism and anabolic metabolism progress. Through various mechanisms Akt, ERK and mTORC1 stimulate aerobic glycolysis, lipid synthesis, the pentose phosphate, oxidative phosphorylation, autophagy, thus producing the major components necessary for cell growth and proliferation. These networks of signaling cascades, their interconnection and regulation allow the cells to maintain energetic balance and allow for the physiological adaptation to the ever-changing environment.