Glutathione Dysregulation in Breast Cancer: A Systematic Review of the Dichotomy between Tumoral Accumulation and Systemic Depletion

Abstract

Introduction: Glutathione (GSH) metabolism is central to cellular redox homeostasis. In breast cancer, its role is paradoxical, acting as a protective antioxidant in healthy cells but promoting malignancy and therapeutic resistance in cancer cells. This systematic review aims to synthesize the evidence on GSH levels in women with breast cancer, focusing on the divergent profiles observed in tumor tissue versus systemic circulation.

Methods: A systematic search was conducted in PubMed, Google Scholar, Semanthic Scholar, Springer, Wiley Online Library for observational studies comparing GSH levels in breast cancer patients (tumor tissue or blood/serum) with corresponding controls (adjacent non-tumor tissue or healthy individuals). Studies were selected based on predefined PICO criteria. Data on GSH concentrations, related enzyme activities, and clinicopathological correlations were extracted. Methodological quality was assessed using the Newcastle-Ottawa Scale.

Results: A total of 18 studies met the inclusion criteria. A consistent and significant pattern of compartmentalized dysregulation was identified. In tumor tissue, levels of reduced GSH, oxidized glutathione (GSSG), and total glutathione were significantly elevated compared to adjacent non-malignant tissue. Conversely, in the systemic circulation (serum, plasma, and erythrocytes), levels of reduced GSH were significantly depleted in breast cancer patients compared to healthy controls, accompanied by elevated GSSG and a consequently lower GSH/GSSG ratio, indicative of systemic oxidative stress. This was further supported by depleted total antioxidant status (TAS) and elevated levels of the lipid peroxidation marker malondialdehyde (MDA) in patients. Activities of key enzymes, including Glutathione Peroxidase (GPx) and Glutathione S-Transferase (GST), were generally elevated in patients. High tumoral GSH levels were associated with advanced disease stage and metastatic progression.

Discussion: The evidence supports a model where in breast cancer cells upregulate GSH biosynthesis as an adaptive mechanism to survive high intrinsic oxidative stress, which confers a growth advantage and resistance to therapy. This tumoral "GSH sink" likely contributes to the depletion of circulating GSH and its precursors, exacerbating systemic oxidative stress. This dichotomy has significant implications, suggesting that while systemic GSH levels may serve as a diagnostic or monitoring biomarker, intratumoral GSH represents a key therapeutic target for overcoming chemo- and radioresistance.

Conclusion: Glutathione metabolism in breast cancer is characterized by a significant dichotomy: tumoral accumulation and systemic depletion. This review consolidates the evidence for this phenomenon and highlights the potential of exploiting this metabolic rewiring for both diagnostic and therapeutic strategies.