Role of Glucose Metabolic Reprogramming in Breast Cancer Progression and Drug Resistance

Abstract

The involvement of glucose metabolic reprogramming in breast cancer progression, metastasis, and therapy resistance has been increasingly appreciated. Studies in recent years have revealed molecular mechanisms by which glucose metabolic reprogramming regulates breast cancer. To date, despite a few metabolism-based drugs being tested in or en route to clinical trials, no drugs targeting glucose metabolism pathways have yet been approved to treat breast cancer. Here, we review the roles and mechanisms of action of glucose metabolic reprogramming in breast cancer progression and drug resistance. In addition, we summarize the currently available metabolic inhibitors targeting glucose metabolism and discuss the challenges and opportunities in targeting this pathway for breast cancer treatment.

Keywords: Warburg effect; breast cancer; drug resistance; glucose metabolism; metabolic inhibitor; metastasis; reverse Warburg effect; tumor microenvironment.

Figure 1

Characteristics of breast cancer subtypes. Different subtypes of breast cancer vary in terms of metabolism, prognosis, receptor expression, and treatments. The luminal-A and luminal-B subtypes tend to undergo the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation, while the basal-like and HER2+ subtypes tend to undergo glycolysis.

Figure 2

Glucose metabolism in cancer cells. The flux of glucose metabolism in cancer cells is characterized by an increase in glucose uptake and aerobic glycolysis, involving a series of reactions that convert glucose into pyruvate. The red color indicates enzymes that are overexpressed in breast cancer cells. The thick arrow indicates the favored flux in breast cancer cells. The thin arrow indicates the unfavored flux in breast cancer cells. The curved arrows indicate the TCA cycle. The dotted arrow indicates the serine biosynthesis pathway. HK: hexokinase; G6P: glucose 6-phosphate; F6P: fructose 6-phosphate; UDP-GlcNAc: uridine diphosphate N-acetylglucosamine; GPI: glucose-6-phosphate isomerase; Rib-5P: ribofuranose 5-phosphate; PFK: phosphofructokinase; F1,6BP: fructose 1,6-bisphosphate; F2,6BP: fructose 2,6-bisphosphate; G3P: glyceraldehyde 3-phosphate; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; 1,3BPG: 1,3-bisphosphoglycerate; PGK: phosphoglycerate kinase; 3PG: 3-phosphoglyceric acid; PHGDH: phosphoglycerate dehydrogenase; PGAM: phosphoglycerate mutase; 2PG: 2-phosphoglycerate; ENO: enolase; PEP: polyestradiol phosphate; PK: pyruvate kinase; LDH: lactate dehydrogenase; 3P-HydPyr: 3-phosphonooxypyruvate; PDC: pyruvate dehydrogenase complex; PDK: pyruvate dehydrogenase kinase; TCA cycle: tricarboxylic acid cycle; PPP: pentose phosphate pathway.

Figure 3

Glucose metabolic crosstalk between breast cancer cells and the tumor microenvironment. Glucose metabolic crosstalk between breast cancer (BC) cells and tumor-associated macrophages (TAMs), tumor-infiltrating T cells (TILs), or cancer-associated fibroblasts (CAFs) is mediated by glucose metabolites such as lactate and pyruvate. Lactate can contribute to the transition of macrophages from M1-like to M2-like, while acting as a double-edged sword in modulating T cells. CAFs undergo a reverse Warburg effect, producing lactate and pyruvate which are taken up by breast cancer cells to promote their proliferation. The upward arrow indicates increased activity in the specific metabolic pathway–glycolysis or oxidative phosphorylation (OXPHOS).