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Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer
Michael J Lukey1, Ahmad A Cluntun2, William P Katt1
1Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.
Abstract:
Efforts to target glutamine metabolism for cancer therapy have focused on the glutaminase isozyme GLS. The importance of the other isozyme, GLS2, in cancer has remained unclear, and it has been described as a tumor suppressor in some contexts. Here, we report that GLS2 is upregulated and essential in luminal-subtype breast tumors, which account for >70% of breast cancer incidence. We show that GLS2 expression is elevated by GATA3 in luminal-subtype cells but suppressed by promoter methylation in basal-subtype cells. Although luminal breast cancers resist GLS-selective inhibitors, we find that they can be targeted with a dual-GLS/GLS2 inhibitor. These results establish a critical role for GLS2 in mammary tumorigenesis and advance our understanding of how to target glutamine metabolism in cancer.
Insights
Glutaminase 2 (GLS2) is crucial in most breast cancers, unlike previously thought. A dual inhibitor targeting both GLS and GLS2 shows promise for treating these tumors.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Glutamine metabolism is a key target for cancer therapy, primarily focusing on the glutaminase (GLS) enzyme.
- The role of the GLS isozyme, GLS2, in cancer has been less understood, with some studies suggesting it acts as a tumor suppressor.
Purpose of the Study:
- To investigate the role of GLS2 in different subtypes of breast cancer.
- To determine the therapeutic potential of targeting GLS2 in breast cancer treatment.
Main Methods:
- Analysis of GLS2 expression in luminal and basal subtype breast tumors.
- Investigation of GATA3 regulation and promoter methylation in GLS2 expression.
- Testing the efficacy of a dual GLS/GLS2 inhibitor against luminal breast cancer cells.
Main Results:
- GLS2 is upregulated and essential in luminal-subtype breast tumors, which constitute the majority of breast cancer cases.
- GLS2 expression is positively regulated by GATA3 in luminal cells and negatively regulated by promoter methylation in basal cells.
- Luminal breast cancers, resistant to GLS-specific inhibitors, are susceptible to a dual GLS/GLS2 inhibitor.
Conclusions:
- GLS2 plays a critical role in mammary tumorigenesis, particularly in luminal breast cancers.
- Targeting GLS2, in combination with GLS, offers a novel therapeutic strategy for a significant subset of breast cancer patients.
