Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer

Abstract

In recent years, diabetes-associated breast cancer has become a significant clinical challenge. Diabetes is not only a risk factor for breast cancer but also worsens its prognosis. Patients with diabetes usually show hyperglycemia and hyperinsulinemia, which are accompanied by different glucose, protein, and lipid metabolism disorders. Metabolic abnormalities observed in diabetes can induce the occurrence and development of breast cancer. The changes in substrate availability and hormone environment not only create a favorable metabolic environment for tumorigenesis but also induce metabolic reprogramming events required for breast cancer cell transformation. Metabolic reprogramming is the basis for the development, swift proliferation, and survival of cancer cells. Metabolism must also be reprogrammed to support the energy requirements of the biosynthetic processes in cancer cells. In addition, metabolic reprogramming is essential to enable cancer cells to overcome apoptosis signals and promote invasion and metastasis. This review aims to describe the major metabolic changes in diabetes and outline how cancer cells can use cellular metabolic changes to drive abnormal growth and proliferation. We will specifically examine the mechanism of metabolic reprogramming by which diabetes may promote the development of breast cancer, focusing on the role of glucose metabolism, amino acid metabolism, and lipid metabolism in this process and potential therapeutic targets. Although diabetes-associated breast cancer has always been a common health problem, research focused on finding treatments suitable for the specific needs of patients with concurrent conditions is still limited. Most studies are still currently in the pre-clinical stage and mainly focus on reprogramming the glucose metabolism. More research targeting the amino acid and lipid metabolism is needed.

Keywords: breast cancer; cancer metabolism; diabetes; hyperglycemia; metabolic reprogramming.

Figure 1

Potential targets of glucose metabolism pathway in metabolic reprogramming of breast cancer. Ⓐ Metformin’s mechanism of action in BC includes inhibiting GLUT1, inhibiting mTORC1, and shifting mitochondrial oxidative phosphorylation to aerobic glycolysis to increase the effect of MCT4i. Ⓑ GLUT1 and GLUT2 inhibitors inhibit the glucose influx to cancer cells. Ⓒ Downregulation of the transporter using transcriptional co-regulator RIP140, shRNA, and miRNA. There are no inhibitors of GLUT3, GLUT4 and GLUT12 suitable for BC yet. Ⓓ SGLT2 inhibitors inhibit the influx of glucose into BC cells. There is no selective SGLT1 inhibitor for BC yet but downregulation of the transporter by siRNA is found to be effective to inhibit BC growth. Ⓔ MCT1i inhibits the bidirectional transport of lactate. MCT4i inhibits lactate export, triggers intracellular acidification, and inhibits cell growth. Ⓕ IR and IGF-1R antagonists inhibit binding of insulin and IGF, thus inhibiting the mTOR signaling pathway which induces tumorigenesis. They also inhibit glucose uptake in cells. Ⓖ IGF1R triggers the PI3K/AKT and MAPK pathway which induces Cyr61 transcription and promotes BC growth. Antibody 093G9 is a potential therapy inhibiting Cyrs61.

Figure 2

Possible MRS target in amino acid metabolism for DM-associated BC. Ⓐ In cancer cells, serine is used for energy production and biomass synthesis during aerobic glycolysis. Inhibiting enzymes that synthesize serine, such as phosphoglycerate dehydrogenase (PHGDH), may inhibit breast cancer growth. New inhibitors of PHGDH, such as CBR-5884 and NCT-503, have been developed and may have potential for use in breast cancer treatment. Ⓑ Glutamine and glutamate are non-essential amino acids that can be synthesized by the body and are involved in both diabetes and cancer. Glutamine can be converted to alpha-ketoglutarate, which is involved in the tricarboxylic acid cycle, while glutamate is necessary for the synthesis of new amino acids. In breast cancer, reducing the uptake of glutamine by inhibiting the ASCT2/SLC1A5 transporter has been shown to halt mTORC1 signaling and cell cycle progression, potentially inhibiting cancer cell growth. Ⓒ Cysteine is an amino acid that is involved in several important pathways in the body, including the metabolism of methionine and the production of glutathione. It has been proposed as a potential therapy target for BC, particularly for TNBC. Cysteine deprivation has been shown to cause programmed necrosis in BC cells that are dependent on cysteine, by inhibiting their ability to produce glutathione and protect against oxidative stress. Additionally, the cysteine transporter SLC3A1 has been found to regulate BC tumorigenesis by reducing the ability of cancer cells to survive under oxidative stress. Ⓓ Arginine is a semi-essential amino acid that has potential as a target for the treatment of diabetes-associated breast cancer. Arginine is taken up by cancer cells via cationic amino acid transporters, and enzymes that break down arginine, such as HuArgI (Co)-PEG5000 and arginine deaminase-PEG 20, have shown promise in treating solid tumors such as breast, ovarian, and pancreatic cancers. Ⓔ Asparagine is a non-essential amino acid that plays a role in cell metabolism and may be a potential target for the treatment of diabetes-associated breast cancer. Asparagine depletion or inhibition may be necessary to fully disrupt cancer cell metabolism when using glutamine restriction as a metabolic targeted therapy. L-asparaginase enzymes, which deplete plasma L-asparagine, have been used to treat acute lymphoblastic leukemia, but they can cause severe side effects due to their toxicity and immunogenicity. Ⓕ Leucine is an essential amino acid that may play a role in the development of type 2 diabetes and cancer. Leucine can activate the mTORC1 pathway, which is involved in cell proliferation, growth, and tumorigenesis. The L-type amino acid transporter (LAT1) is a cancer prognostic marker and a potential target for breast cancer treatment. LAT1 inhibitors such as JPH203 have been shown to inhibit cell proliferation and increase the sensitivity of breast cancer cells to radiation therapy. Figure abbreviation: PHGDH: phosphoglycerate dehydrogenase; 3PG:3-Phosphoglyceric acid; PAST1: Putative achaete scute target 1; PSPH: Phosphoserine phosphatase; SHMT: Serine hydroxymethyltransferase; GLS: glutaminase; α-KG: α-ketoglutarate; OAA: Oxaloacetic acid; LAT1: L-type amino acid transporter; ADI: Arginine deiminase; Arg1: Arginase 1.