Journal article
Glutathione peroxidase 4 (GPX4) and obesity interact to impact tumor progression and treatment response in triple negative breast cancer
Cancer & metabolism, Vol.13(1), 11
02/25/2025
DOI: 10.1186/s40170-025-00380-8
PMCID: PMC11863593
PMID: 40001204
Abstract
Triple-negative breast cancer (TNBC), which tends to be more advanced when diagnosed and more aggressive than other breast cancer subtypes, is accelerated by obesity. Hypertrophic adipocytes and cancer cells exhibit increased oxidative stress and altered redox homeostasis, influencing therapeutic outcomes. Enzymes implicated in both redox regulation and TNBC include glutathione peroxidase 4 (GPX4; reduces lipid peroxides) and pyruvate carboxylase (PC; essential in oxidative stress protection). Using preclinical models, we characterized interactions between GPX4, PC, and oxidative stress in TNBC cells, and established effects of GPX4 suppression on TNBC progression. In TNBC cells, PC knockdown increased GPX4 expression, while GPX4 knockdown increased PC expression. GPX4 inhibition by erastin or RSL3 enhanced TNBC cell death in vitro, and antioxidants mitigated the cytotoxicity. In obese mice, GPX4 knockdown, versus scramble control: (i) reduced tumor burden following orthotopic transplantation of TNBC cells; and (ii) reduced lung metastasis following tail vein injection of TNBC cells in combination with chemotherapy (carboplatin) but not immunotherapy (anti-CTLA4 plus anti-PD1). We conclude that GPX4 and PC expression are inversely related in TNBC cells, and GPX4 and obesity interact to impact TNBC progression and treatment responses. Moreover, GPX4-mediated redox defense, alone or in combination with chemotherapy, is a targetable vulnerability for treating TNBC, including obesity-related TNBC.
GPX4 suppression, alone or with current TNBC therapies, impacts outcomes in preclinical TNBC models with or without obesity and offers a new, plausible mechanistic target for TNBC treatment.
Details
- Title: Subtitle
- Glutathione peroxidase 4 (GPX4) and obesity interact to impact tumor progression and treatment response in triple negative breast cancer
- Creators
- Emily N Devericks - University of North Carolina at Chapel HillBennett H Brosnan - University of North Carolina at Chapel HillAlyssa N Ho - University of North Carolina at Chapel HillElaine M Glenny - University of North Carolina at Chapel HillHannah M Malian - University of North Carolina at Chapel HillDorothy Teegarden - Purdue University West LafayetteMichael K Wendt - University of IowaMichael F Coleman - University of North Carolina at Chapel HillStephen D Hursting - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- Cancer & metabolism, Vol.13(1), 11
- DOI
- 10.1186/s40170-025-00380-8
- PMID
- 40001204
- PMCID
- PMC11863593
- NLM abbreviation
- Cancer Metab
- ISSN
- 2049-3002
- eISSN
- 2049-3002
- Publisher
- BMC
- Grant note
- R01CA271597 / NCI NIH HHS Center for Triple Negative Breast Cancer / Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill 5F31CA275336-02 / NCI NIH HHS R01 CA271597 / NCI NIH HHS P30 CA016086 / NCI NIH HHS
- Language
- English
- Date published
- 02/25/2025
- Academic Unit
- Holden Comprehensive Cancer Center; Internal Medicine
- Record Identifier
- 9984795475402771
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