THE ROLE OF GLUTATHIONE PEROXIDASE 4 AT THE INTERFACE OF TUMOR METABOLISM, DIET-INDUCED OBESITY, AND TREATMENT EFFICACY IN TRIPLE NEGATIVE BREAST CANCER

Reactive oxygen species are a double-edged sword – they are the products of several metabolic processes required to sustain life, but in excess can cause oxidative damage. Breast cancer remains the second-leading cause of cancer-related death in the US. Obesity is an established risk factor for several aggressive breast cancer subtypes, and is also associated with increased breast cancer metastasis and mortality. On a mechanistic level, hypertrophic adipocytes and cancer cells exhibit oxidative stress and altered redox homeostasis, influencing therapeutic outcomes. While oxidative stress contributes to cancer progression, understanding the complex interplay between obesity-induced metabolic changes and redox signaling in triple negative breast cancer (TNBC) presents a unique opportunity to develop targeted therapeutic strategies for this historically treatment-resistant disease.In this dissertation, we aimed to understand how obesity and TNBC, both as metabolic diseases, affect lipid-specific oxidative stress in the context of tumor metabolism and response to current front-line therapies. Using preclinical models, we characterized a specific metabolic interaction between oxidative stress and TNBC, and established the effect of lipid oxidative stress on TNBC progression. We then utilized this metabolic interaction to identify a mechanism by which tumor burden can be reduced more effectively in obese mice following orthotopic transplantation of TNBC cells. Finally, we utilized front-line therapies, including chemotherapy (carboplatin) and immunotherapy (anti-CTLA4 plus anti-PD1), to identify lipid oxidative stress as a critical regulator of treatment response specifically in the context of obesity. These findings identify a mechanism of lipid oxidative stress by which tumor progression and treatment response can be altered specifically in obesity-driven TNBC. Moreover, we demonstrate that targeting lipid-mediated redox defense, alone or in combination with current anticancer therapies, represents a promising therapeutic strategy for TNBC, particularly in the context of obesity.