High Expression of NRF2 Is Associated with Increased Tumor-Infiltrating Lymphocytes and Cancer Immunity in ER-Positive/HER2-Negative Breast Cancer

SIMPLE SUMMARY: The clinical relevance of Nuclear factor erythroid 2-Related Factor 2 (NRF2) in human breast cancer remains unclear. A total of 5443 breast cancer patients with transcriptomic profile were analyzed for the clinical relevance of NRF2 expression, including cancer aggressiveness, immune cell infiltration, patient survival, and drug response. We found that tumors with high NRF2 expression were associated with better survival in ER-positive/HER2-negative breast cancer. NRF2 expression was equivalent in immune, stromal, and cancer cells in tumor microenvironment. We found that high NRF2 expression was associated with enhanced tumor-infiltrating lymphocytes in ER-positive/HER2-negative breast cancer. NRF2 expression significantly correlated with drug sensitivity in multiple ER-positive breast cancer cell lines, but not associated with pathological complete response after neoadjuvant chemotherapy in breast cancer patients regardless of subtypes. ABSTRACT: Nuclear factor erythroid 2-related factor 2 (NRF2) is a key modifier in breast cancer. It is unclear whether NRF2 suppresses or promotes breast cancer progression. We studied the clinical relevance of NRF2 expression by conducting in silico analyses in 5443 breast cancer patients from several large patient cohorts (METABRIC, GSE96058, GSE25066, GSE20194, and GSE75688). NRF2 expression was significantly associated with better survival, low Nottingham pathological grade, and ER-positive/HER2-negative and triple negative breast cancer (TNBC). High NRF2 ER-positive/HER2-negative breast cancer enriched inflammation- and immune-related gene sets by GSEA. NRF2 expression was elevated in immune, stromal, and cancer cells. High NRF2 tumors were associated with high infiltration of immune cells (CD8(+), CD4(+), and dendritic cells (DC)) and stromal cells (adipocyte, fibroblasts, and keratinocytes), and with low fraction of Th1 cells. NRF2 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 NRF2 and pathologic complete response (pCR) rate after neoadjuvant chemotherapy in human samples. Finally, high NRF2 breast cancer was associated with high expression of immune checkpoint molecules. In conclusion, NRF2 expression was associated with enhanced tumor-infiltrating lymphocytes in ER-positive/HER2-negative breast cancer.