SLC1A5 is a key regulator of glutamine metabolism and a prognostic marker for aggressive luminal breast cancer.

Cancer cells exhibit altered metabolism, often relying on glutamine (Gln) for growth. Breast cancer (BC) is a heterogeneous disease with varying clinical outcomes. We investigated the role of the amino acid transporter SLC1A5 (ASCT2) and its association with BC subtypes and patient outcomes. In large BC cohorts, SLC1A5 mRNA (n = 9488) and SLC1A5 protein (n = 1274) levels were assessed and correlated their expression with clinicopathological features, molecular subtypes, and patient outcomes. In vitro SLC1A5 knockdown and inhibition studies in luminal BC cell lines (ZR-75-1 and HCC1500) were used to further explore the role of SLC1A5 in Gln metabolism. Statistical analysis was performed using chi-squared tests, ANOVA, Spearman's correlation, Kaplan-Meier analysis, and Cox regression. SLC1A5 mRNA and SLC1A5 protein expression were strongly correlated in luminal B, HER2 + and triple-negative BC (TNBC). Both high SLC1A5 mRNA and SLC1A5 protein expression were associated with larger tumour size, higher grade, and positive axillary lymph node metastases (P < 0.01). Importantly, high SLC1A5 expression correlated with poor BC-specific survival specifically in the highly proliferative luminal subtype (P < 0.001). Furthermore, SLC1A5 knockdown by siRNA or GPNA inhibition significantly reduced cell proliferation and glutamine uptake in ZR-75-1 cells. Our findings suggest SLC1A5 plays a key role in the aggressive luminal BC subtype and represents a potential therapeutic target. Further research is needed to explore SLC1A5 function in luminal BC and its association with Gln metabolism pathways.