Triple-negative breast cancer (TNBC) is account for 10∼25% of breast cancer incidence with more aggressive phenotype, metastatic capability, and poorer prognosis than other subtypes. Altered cancer metabolism is an emerging hallmark of cancer. Previous studies reported that TNBC cells exhibit greater aerobic glycolysis than non-TNBC cells; however, the detailed regulatory mechanism is largely unknown.
The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to analyze expression of glycolytic genes and clinical relevance in TNBC patients. Immunohistochemistry assay was performed to confirm the expression of glycolytic gene in breast cancer tissues. Gain-of-function and loss-of-function studies were conducted in TNBC cell lines. The effect of inflammatory microenvironment was carried out by coculture of macrophages and TNBC cells, and the expression of inflammatory cytokines were performed by real-time PCR.
We compared the differential genes expression in TNBC and non-TNBC by in silico analysis. Interestingly, the expression of glucose transporter 3 (Glut3) is upregulated in TNBC patients, compared to non-TNBC patients. Mechanistically, overexpression of Glut3 regulated the expression of epithelial-mesenchymal transition (EMT) genes and promoted invasiveness and metastasis of TNBC cells. Activation of IL6/STAT3 signaling regulates the expression of Glut3 and glycolytic genes, and coexpression of IL6/Glut3 rendered poorer survival outcome, particularly in TNBC. Moreover, conditioned medium (CM) from Glut3-expressing tumor cells induced macrophage activation and production of pro-inflammatory cytokines, and patients with high Glut3 level associated with inflammaotry signautres.
Upregulation of IL6/STAT3 signaling axis promotes expression of Glut3 and glycolytic genes. Elevation of Glut3 in TNBC induces macrophage activation and production of pro-inflammatory cytokines. Our data show the possible association between glucose metabolism and inflammatory microenvironment in TNBC.
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Legal entity responsible for the study
Ministry of Science and Technology, Taiwan.
The author has declared no conflicts of interest.