Background: Glutamine metabolism has a key role in the regulation of uncontrolled tumour growth by modulating bioenergetics, redox homeostasis and serving as a precursor for biomass synthesis. Glutaminase is a key enzyme involved in glutaminolysis, a process which plays a crucial role in carcinogenesis and progression. This study aimed to evaluate the expression and prognostic significance of glutaminase in luminal breast cancer (BC).
Methods: The glutaminase protein isoforms (GLS and GLS2) were assessed at the genomic and transcriptomic levels, using METABRIC (n=1398) and GENE MINER datasets (n=4,712), and protein level using immunohistochemistry in large well characterised cohorts of luminal Oestrogen Receptor (ER)-positive and HER2-negative BC patients, including ductal carcinoma in situ (DCIS) (n=206) and invasive BC (IBC; n=717) cohorts. GLS and GLS2 expression was associated with clinicopathological features, patient outcome and other glutamine-metabolism related genes.
Results: In DCIS, GLS expression was an independent risk factor for shorter local recurrence-free interval (p<0.0008). In IBC high GLS and GLS2 mRNA and protein expression significantly correlated with solute carriers with high glutamine affinity, SLC3A2 (p≤0.01) SLC7A8 (p≤0.01) and SLC7A5 (p<0.001), and glutamine related enzymes; GLUD1 (p<0.001) and ALDH18A1 (p<0.001). GLS and GLS2 gene copy number gains were associated with poor patient outcome (p=0.028; p=0.010 respectively). High GLS2 protein was predictive of a longer disease-free survival (p=0.006).
Conclusion: GLS appears to play a role in the early non-invasive stage of BC and it could be used as a potential biomarker to predict DCIS progression to invasive disease. In IBC, both GLS and GLS2 play a key role in the biological function of luminal tumours. Further functional assessments are needed to explore the specific role played by each isoform in BC.