Glutamine transporter SLC38A3 promotes breast cancer metastasis via Gsk3β/β-catenin/EMT pathway

Breast cancer is the leading cancer-related cause of death in women. Here we show that solute carrier family 38-member 3 (SLC38A3) is overexpressed in breast cancer, particularly in triple-negative breast cancer (TNBC) cells and tissues. Our study reveals that SLC38A3 regulates cellular glutamine, glutamate, asparagine, aspartate, alanine, and glutathione (GSH) levels in breast cancer cells. Our data demonstrate that SLC38A3 enhances cell viability, cell migration and invasion in vitro, and promotes tumor growth and metastasis in vivo, while reducing apoptosis and oxidative stress. Mechanistically, we show that SLC38A3 suppresses the activity of glycogen synthase kinase 3-β (Gsk3β), a negative regulator of β-catenin, and increases protein levels of β-catenin, leading to the upregulation of epithelial-to-mesenchymal-transition (EMT)-inducing transcription factors and EMT markers in breast cancer. In summary, we show that SLC38A3 is overexpressed in breast cancer and promotes breast cancer metastasis via the GSK3β/β-catenin/EMT pathway, presenting a novel therapeutic target to explore for breast cancer. •Solute carrier family 38-member 3 (SLC38A3) mRNA and protein expression levels are consistently overexpressed in TNBC.•SLC38A3 regulates cellular glutamine, glutamate, asparagine, aspartate, alanine, and glutathione (GSH) levels in TNBC cells.•SLC38A3 enhances cell viability, cell migration and invasion, and reduces apoptosis and oxidative stress in vitro.•SLC38A3 promotes tumor growth and metastasis in vivo.•SLC38A3 promotes breast cancer metastasis via the GSK3β/β-catenin/EMT pathway. We show that SLC38A3 is overexpressed in breast cancer and positively regulates neutral amino acid levels, cell viability, antioxidant levels, anti-apoptosis, cell migration and invasion and metastasis via Gsk3β/β-catenin/EMT pathway in breast cancer, which could be further explored as a novel therapeutic target for breast cancer.