Overexpressed CFLAR drives 5-fluorouracil sensitivity and immune response in breast cancer by regulating reactive oxygen species

Breast cancer (BRCA), the most frequent malignancy in women, is a highly heterogeneous disease. Chemoresistant is the main factor for the BRCA treatment failure. However, the mechanism underlying chemoresistant is still unclear. In this study, we performed comprehensive bioinformatics to verify differentially expressed cell death genes between BRCA and normal tissues. CFLAR was down-regulated in BRCA patients and high expression level of CFLAR exhibited improved prognosis in BRCA patients. CFLAR played a key role in regulating tumor growth. However, the role of CFLAR in different BRCA subtype and its influence in drug resistance and immune therapy need further clarification. CFLAR was decreased in Ki67 positive patients and increased in ER and PR positive patients. CFLAR was significantly down-regulated in Luminal and TNBC than normal breast tissue. CFALR is higher in drug respond patients than drug non-respond patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that aberrantly expressed CFLAR was potentially linked with oxidative phosphorylation, T cell receptor signaling pathway, NADH dehydrogenase (ubiquinone) activity, NADH dehydrogenase (quinone) activity, oxidoreductase activity and oxidoreductase-driven active transmembrane transporter activity. Through cell colony formation experiment, overexpression of CFLAR could inhibit reactive oxygen species (ROS) upon 5-FU treatment and promote 5-FU sensitivity in BT-549 and MDA-MB-231cells. In addition, we verified that CFLAR expression was positively correlated with Tcm, T helper cells, Tem, T cells, B cells NK CD56 bright cells and Th2 cells, especially CD8 + T cells. CFALR was higher in CAR-T response patients, anti-PD-L1 response patients and anti-PD1 patients. In summary, CFLAR could regulated ROS homeostasis and ameliorates 5-FU sensitivity of breast cancer cell. CFLAR may be a novel therapeutic target in BRCA.