Hyperglycemia and Chemoresistance in Breast Cancer: From Cellular Mechanisms to Treatment Response

Abstract

Female breast cancer is a complex, multifactorial disease. Studies have shown that hyperglycemia is one of the most important contributing factors to increasing the risk of breast cancer that also has a major impact on the efficacy of chemotherapy. At the cellular level, hyperglycemia can promote the proliferation, invasion, and migration of breast cancer cells and can also induce anti-apoptotic responses to enhance the chemoresistance of tumors via abnormal glucose metabolism. In this article, we focus on the latest progress in defining the mechanisms of chemotherapy resistance in hyperglycemic patients including the abnormal behaviors of cancer cells in the hyperglycemic microenvironment and the impact of abnormal glucose metabolism on key signaling pathways. To better understand the advantages and challenges of breast cancer treatments, we explore the causes of drug resistance in hyperglycemic patients that may help to better inform the development of effective treatments.

Keywords: breast cancer; chemoresistance; chemotherapy resistance; glucose metabolism; hyperglycemia.

Figure 1

Summary of the cellular metabolic effects of hyperglycemia in cancer. GLUT1, Glucose transporter 1; PPP, Pentose phosphate pathway; EGFR, Epidermal growth factor receptor; IF, Inflammatory factors; TF, Transcription factors; HIF, Hypoxia-inducible factor-1; HK2, Hexokinase2; PKM1, Pyruvate kinase M1; EMT, Epithelial-mesenchymal transition; FASN/FAS, Fatty acid synthase; ER, Estrogen receptor; IGF, Insulin growth factor; PI3K, Intracellular phosphatidylinositol kinase; AKT, Protein kinase B; mTOR, Mammalian target of rapamycin; Grb2, Growth factor receptor-bound protein2; MAPK, Mitogen-activated protein kinase.

Figure 2

The anti-apoptotic mechanisms of hyperglycemia. Activation of anti-apoptotic genes promotes chemotherapeutic drug resistance. PPP, Pentose phosphate pathway; HIPK2, Homologous domain interacting protein kinase1; Erk, extracellular regulated protein kinase; P53, a tumor suppressor gene.

Figure 3

Schematic representation of the resistance mechanisms of common chemotherapeutic drugs in the hyperglycemic environment. The dotted line represents the route in the text. ADR, Adriamycin; FGF/FGFR, Fibroblast growth factor and its receptor; FRS, Fibroblast growth factor receptor substrate; IGFBP-1, Insulin-like growth factor-binding protein-1; ABC protein, ATP binding cassette transporter; P-glycoprotein; AMPK, AMP-activated protein kinase; PKM2, Pyruvate kinase M2; HSF1, Heat shock factor1; LDHA, Lactate dehydrogenase.

Figure 4

Cancer cells in the acidic microenvironment can escape the immune system and eventually lead to tumor progression. Inflammatory factor, IL6, TNF-α, COX-2 and so on; RDS, Reactive oxygen species; MIF, Migration inhibitory factor; VEGF, Vascular endothelial growth factor; UDP-sugar, Uridine diphosphate glucose; G-CSF, Granulocyte colony stimulating factor; GM-CSF, Granulocyte macrophage colony stimulating factor; MDSCs, Myeloid-derived suppressor cells; EV, Extracellular vesicle, transmit myeloid-specific lncRNA and HIF-1α-stabilizing lncRNA.