Abstract
PURPOSE: Reactive oxygen species (ROS) are oxygen-containing molecules that have high reactivity and play roles in protection or harm the cancer cells. We aimed to clarify the clinical relevance of ROS in breast cancer (BC) tumor microenvironment (TME). We hypothesized that it is associated with worse BC patient outcomes. METHODS: ROS score was generated by Gene Set Variation Analysis of Hallmark ROS pathway gene set and a total of 6245 BC patients were analyzed. RESULTS: High ROS BC significantly enriched cell proliferation-related gene sets (MYC targets v1 and v2, G2M checkpoint, E2F targets), pro-cancer-related gene sets (DNA repair, unfolded protein response, MTORC1 signaling, PI3K/AKT/MTOR signaling, glycolysis, and oxidative phosphorylation), immune-related gene sets (inflammatory response, allograft rejection, interferon-α and γ responses, complement, and IL6/JAK/STAT3 signaling), and infiltrated immune cells (CD4(+) memory and CD8(+) T cells, Th1 and Th2, dendritic cells, Tregs, M1 and M2 macrophages) and B cells, as well as elevated cytolytic activity consistently in both METABRIC and GSE96058 cohorts. Cancer cells were the major source of ROS in BC TME of single-cell sequence (GSE75688) cohort. High ROS was associated with intratumor heterogeneity, homologous recombination defects, mutation rates, and neoantigens, and with clinical aggressiveness in AJCC stage, Nottingham grade and Ki67 expression, as well as worse overall survival in both GSE96058 and METABRIC, and with worse disease-specific survival in METABRIC. CONCLUSION: Abundant ROS in BC patients is associated with abundant mutations, aggressive cancer biology, immune response, and worse survival.