Obesity-Related Inflammation Reduces Treatment Sensitivity and Promotes Aggressiveness in Luminal Breast Cancer Modulating Oxidative Stress and Mitochondria

Abstract

Background: Obesity, characterized by the secretion of several pro-inflammatory cytokines and hormones, significantly increases the risk of developing breast cancer and is associated with poorer outcomes. Mitochondrial and antioxidant status are crucial in both tumor progression and treatment response. Methods: This study investigates the impact of an ELIT cocktail (17β-estradiol, leptin, IL-6, and TNFα), which simulates the obesity-related inflammation condition in postmenopausal women, using a 3D culture model. We examined the effects of ELIT exposure on mammosphere formation, oxidative stress and mitochondrial markers, and treatment sensitivity in luminal (T47D, MCF7) and triple-negative (MDA-MB-231) breast cancer cell lines. After that, 3D-derived cells were re-cultured under adherent conditions focusing on the mechanisms leading to dissemination and drug sensitivity. Results: Our results indicated that ELIT condition significantly increased mammosphere formation in luminal breast cancer cell lines (from 3.26% to 6.38% in T47D cell line and 0.68% to 2.32% in MCF7 cell line) but not in the triple-negative MDA-MB-231 cell line. Further analyses revealed a significant decrease in mitochondrial and antioxidant-related markers, particularly in the T47D cell line, where higher levels of ESR2, three-fold increased by ELIT exposure, may play a critical role. Importantly, 3D-derived T47D cells exposed to ELIT showed reduced sensitivity to tamoxifen and paclitaxel, avoiding a 34.2% and 75.1% reduction in viability, respectively. Finally, through in silico studies, we identified specific biomarkers, including TOMM20, NFE2L2, CAT, and ESR2, correlated with poor prognosis in luminal breast cancer. Conclusions: Taken together, our findings suggest that antioxidant and mitochondrial markers are key factors that reduce treatment sensitivity in obesity-related luminal breast cancer. The identified biomarkers may serve as valuable tools for the prognosis and development of more effective therapies in these patients.