| Summary: | Nuclear factor erythroid 2-related factor 2 (<i>NRF2</i>) is a key modifier in breast cancer. It is unclear whether NRF2 suppresses or promotes breast cancer progression. We studied the clinical relevance of <i>NRF2</i> expression by conducting in silico analyses in 5443 breast cancer patients from several large patient cohorts (METABRIC, GSE96058, GSE25066, GSE20194, and GSE75688). <i>NRF2</i> expression was significantly associated with better survival, low Nottingham pathological grade, and ER-positive/HER2-negative and triple negative breast cancer (TNBC). High <i>NRF2</i> ER-positive/HER2-negative breast cancer enriched inflammation- and immune-related gene sets by GSEA. <i>NRF2</i> expression was elevated in immune, stromal, and cancer cells. High <i>NRF2</i> tumors were associated with high infiltration of immune cells (CD8<sup>+</sup>, CD4<sup>+</sup>, and dendritic cells (DC)) and stromal cells (adipocyte, fibroblasts, and keratinocytes), and with low fraction of Th1 cells. <i>NRF2</i> expression significantly correlated with area under the curve (AUC) of several drug response in multiple ER-positive breast cancer cell lines, however, there was no significant association between <i>NRF2</i> and pathologic complete response (pCR) rate after neoadjuvant chemotherapy in human samples. Finally, high <i>NRF2</i> breast cancer was associated with high expression of immune checkpoint molecules. In conclusion, <i>NRF2</i> expression was associated with enhanced tumor-infiltrating lymphocytes in ER-positive/HER2-negative breast cancer.
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