Increased glutamine metabolism (glutaminolysis) is a hallmark of cancer and is recognised as a key metabolic change in cancer cells. Breast cancer is a heterogeneous disease with different morphological and molecular subtypes and responses to therapy, and breast cancer cells are known to rewire glutamine metabolism to support survival and proliferation. Glutaminase isoenzymes (GLS and GLS2) are key enzymes for glutamine metabolism. Interestingly, GLS and GLS2 have contrasting functions in tumorigenesis. In this review, we explore the role of glutaminase in cancer, primarily focusing on breast cancer, address the role played by oncogenes and tumour suppressor genes in regulating glutaminase, and discuss current therapeutic approaches to targeting glutaminase.

BACKGROUND: Cancer cells must alter their metabolism to support proliferation. Immune evasion also plays a role in supporting tumour progression. This study aimed to find whether enhanced glutamine uptake in breast cancer (BC) can derive the existence of specific immune cell subtypes, including the subsequent impact on patient outcome. METHODS: SLC1A5, SLC7A5, SLC3A2 and immune cell markers CD3, CD8, FOXP3, CD20 and CD68, in addition to PD1 and PDL1, were assessed by using immunohistochemistry on TMAs constructed from a large BC cohort (n = 803). Patients were stratified based on SLC protein expression into accredited clusters and correlated with immune cell infiltrates and patient outcome. The effect of transient siRNA knockdown of SLC7A5 and SLC1A5 on PDL1 expression was evaluated in MDA-MB-231 cells. RESULTS: High SLCs were significantly associated with PDL1 and PD1 +, FOXP3 +, CD68 + and CD20 + cells (p < 0.001). Triple negative (TN), HER2 + and luminal B tumours showed variable associations between SLCs and immune cell types (p ≤ 0.04). The expression of SLCs and PDL1, PD1 +, FOXP3 + and CD68 + cells was associated with poor patient outcome (p < 0.001). Knockdown of SLC7A5 significantly reduced PDL1 expression. CONCLUSION: This study provides data that altered glutamine pathways in BC that appears to play a role in deriving specific subtypes of immune cell infiltrates, which either support or counteract its progression.

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