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Metabolic reprogramming is a malignant phenotype of cancer. Cancer cells utilize glycolysis to fuel rapid proliferation even in the presence of oxygen, and elevated glycolysis is coupled to lactate fermentation in the cancer microenvironment. Although lactate has been recognized as a metabolic waste product, it has become evident that lactate functions as not only an energy source but a signaling molecule through the lactate receptor G-protein-coupled receptor 81 (GPR81) under physiological conditions. However, the pathological role of GPR81 in cancer remains unclear. Here, we show that GPR81 regulates the malignant phenotype of breast cancer cell by reprogramming energy metabolism. We found that GPR81 is highly expressed in breast cancer cell lines but not in normal breast epithelial cells. Knockdown of GPR81 decreased breast cancer cell proliferation, and tumor growth. Mechanistically, glycolysis and lactate-dependent ATP production were impaired in GPR81-silenced breast cancer cells. RNA sequencing accompanied by Gene Ontology enrichment analysis further demonstrated a significant decrease in genes associated with cell motility and silencing of GPR81 suppressed cell migration and invasion. Notably, histological examination showed strong expression of GPR81 in clinical samples of human breast cancer. Collectively, our findings suggest that GPR81 is critical for malignancy of breast cancer and may be a potential novel therapeutic target for breast carcinoma.

The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer