# Targeting Glutaminase Isoforms GLS and GLS2 in Luminal Breast Cancer

## TL;DR

This study explores the role of glutaminase in luminal breast cancer and suggests that targeting GLS and GLS2 could be a new treatment approach.

## Contribution

The study identifies GLS and GLS2 as potential therapeutic targets in luminal breast cancer through functional assays.

## Key findings

- Silencing GLS in luminal breast cancer cells reduced proliferation and induced apoptosis.
- GLS2 silencing in luminal B cells reduced proliferation but had no effect on apoptosis or cell cycle.
- CB-839 had little effect on luminal breast cancer cells, suggesting isoform-specific targeting may be needed.

## Abstract

Upregulation of glutaminase enzymatic activity promotes tumour cell proliferation. Its overexpression correlates with poor disease outcome in patients, including those with breast cancer. A selective glutaminase inhibitor, CB-839, which targets cancer cells by blocking glutamine conversion to glutamate, has shown promising preclinical results as a therapeutic target in triple-negative breast cancer treatment. The current study aimed to determine the importance of glutaminase in Oestrogen Receptor positive/luminal breast cancer to potentially identify therapeutic targets to treat this subtype. In vitro studies using luminal breast cancer cells were performed to investigate the effects of siRNA knockdown of glutaminase genes (GLS and GLS2) and inhibition using CB-839 on functional assays. Silencing GLS in luminal breast cancer cells significantly reduced cell proliferation whilst inducing apoptosis. A similar impact on cell proliferation was observed when silencing GLS2 in luminal B cells, but there was no observed effect on cell apoptosis and cell cycle. There was little effect of GLS inhibition using CB-839 in luminal breast cancer. This study demonstrates that glutaminase is necessary for luminal breast cancer growth and survival. Co-targeting GLS and GLS2 might be a novel approach for the treatment of this subclass. Further functional studies to evaluate the underlying molecular mechanisms of this process are warranted.