# Impact of extracellular glutathione catabolism on triple-negative breast cancer

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $60,925

## Abstract

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options. There is
an emerging interest in blocking antioxidants for cancer therapy, but how antioxidants promote cancer growth is
unclear. Glutathione (GSH) is the most abundant antioxidant in the body and our previous work has shown that
GSH promotes tumorigenesis of triple-negative breast cancers (TNBC). It is generally assumed that GSH acts
intracellularly as an antioxidant in cancer cells. However, our preliminary studies show that blocking intracellular
GSH synthesis does not impede TNBC growth. These surprising results suggest an alternative mechanism
where extracellular GSH supports breast tumor growth. The overarching goal of this proposal is to determine
how extracellular GSH promotes tumor growth. It is known that extracellular GSH is present in plasma but cells
cannot import GSH. Instead, GSH is metabolized by gamma-glutamyl transferase (GGT1) to produce a glutamyl-
dipeptide and cysteinylglycine, which yields cystine and glycine. Indeed, we find that ablation of GSH synthesis
in vivo not only lowers circulating GSH but also reduces the levels of cysteinylglycine, cysteine, and glycine in
tissues. Further, we show that supplementation with GSH and cysteinylglycine can rescue TNBC growth upon
cystine depletion in GGT1-dependent and -independent manners, respectively. Together, these preliminary data
suggest an alternative mechanism where GSH functions as a circulating source of metabolites rather than as a
direct antioxidant. In this proposal, we describe experiments that will test the hypothesis that the catabolism of
extracellular GSH by tumor GGT1 supports TNBC growth. In Aim 1, we will elucidate the impact of extracellular
GSH on TNBC growth. In Aim 2, we identify the reliance of TNBC on GGT1-mediated GSH catabolism. In Aim
3, we will determine the mechanisms by which cysteinylglycine supplies cysteine for TNBC growth. Our research
will challenge the paradigm of antioxidant function in cancer by describing a novel mechanism of GSH function
as a circulating source of amino acids. Further, these studies have the potential to reveal a completely new set
of unrealized targets and therapeutic strategies for TNBC.

## Key facts

- **NIH application ID:** 10977459
- **Project number:** 3R01CA269813-03S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Isaac Spencer Harris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $60,925
- **Award type:** 3
- **Project period:** 2022-04-18 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977459

## Citation

> US National Institutes of Health, RePORTER application 10977459, Impact of extracellular glutathione catabolism on triple-negative breast cancer (3R01CA269813-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10977459. Licensed CC0.

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