We provide comprehensive clinical data indicating that the glutamine-proline regulatory axis plays an important role in the aggressive subclass of luminal BC and is therefore a potential therapeutic target.
The glutamine metabolism has a key role in the regulation of uncontrolled tumour growth. This study aimed to evaluate the expression and prognostic significance of glutaminase in luminal breast cancer (BC). The glutaminase isoforms (GLS/GLS2) were assessed at genomic/transcriptomic levels, using METABRIC (n = 1398) and GeneMiner datasets (n = 4712), and protein using immunohistochemistry in well-characterised cohorts of Oestrogen receptor-positive/HER2-negative BC patients: ductal carcinoma in situ (DCIS; n = 206) and invasive breast cancer (IBC; n = 717). Glutaminase expression was associated with clinicopathological features, patient outcome and glutamine-metabolism-related genes. In DCIS, GLS alone and GLS+/GLS2- expression were risk factors for shorter local recurrence-free interval (p < 0.0001 and p = 0.001, respectively) and remained prognostic factors independent of tumour size, grade and comedo necrosis (p = 0.0008 and p = 0.003, respectively). In IBC, GLS gene copy number gain with high mRNA expression was associated with poor patient outcome (p = 0.011), whereas high GLS2 protein was predictive of a longer disease-free survival (p = 0.006). Glutaminase plays a role in the biological function of luminal BC, particularly GLS in the early non-invasive stage, which could be used as a potential biomarker to predict disease progression and a target for inhibition. Further validation is required to confirm these observations, and functional assessments are needed to explore their specific roles.
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.
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