Journal
LIFE SCIENCES
Volume 294, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2022.120370
Keywords
Glucagon-like peptide-1 receptor (GLP-1R); Reactive oxygen species (ROS); NADPH oxidases 4 (NOX4); VEGF; Breast cancer; Liraglutide
Funding
- National Natural Science Foundation of China [31770968, 31800661]
- Open Project Program of Key Laboratory for Tumor Precision Medicine of Shaanxi Province [KLTPM-SX2017-A3, KLTPM-SX2018-B1]
- Open Funds of State Key Laboratory of Oncology in South China
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This study found that liraglutide, at a specific concentration, could promote the malignant progression of breast cancer through activating GLP-1R, potentially exacerbating the risk of triple negative breast cancer. Therefore, the dosage and the phenotype of breast cancer should be considered when administering antidiabetic drugs.
Aims: Scientific evidence imply the strong correlation between diabetes and breast cancer. Glucagon-like peptide-1 (GLP-1) and its analogue liraglutide, have been widely used for diabetes treatment. However, the role of GLP-1 receptor (GLP-1R) in breast cancer requires further elucidation. This study aimed to investigate the risk and the molecular mechanisms of liraglutide using in breast cancer. Materials and methods: Quantitative real-time polymerase chain reaction, western blot or immunohistochemistry were used to detect the expressions of GLP-1R, NADPH oxidase 4 (NOX4) and vascular endothelial growth factor (VEGF) in human triple negative breast cancer (TNBC) cells (MDA-MB-231 and MDA-MB-468) and tissues derived from BALB/cfC3H mouse bearing 4T1 cells inoculation. Cell proliferation and migration was detected using the Cell Counting Kit-8, adenosine triphosphate assay, and transwell assay, respectively. Flow cytometry was used to measure the level of reactive oxygen species (ROS). Key findings: We found that the expression of GLP-1R increased after liraglutide treatment in breast cancer cells and the transplanted tumors. Liraglutide, at a slightly higher concentration, accelerated breast cancer progress in vitro (100 nM) and in vivo (400 mu g/kg) through the NOX4/ROS/VEGF signal pathway after activating GLP-1R. The GLP-1R inhibitor, Exendin (9-39), significantly inhibited the effect of liraglutide, inducing a reversed function of GLP-1R activation. Significance: Our study illustrated that in an approximately toxicology context, liraglutide may promote the malignant progression of TNBC. The dosage and the phenotype of the breast cancer should be considered as important factors for the rational administration of antidiabetic drugs, especially that of liraglutide in breast cancer patients.
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