Background <p>Tamoxifen (TAM) resistance limits favorable outcomes in patients with breast cancer. Bioinformatics results suggest that the miR-548as-5p/nuclear factor kappa B1 (NF-κB1) axis may regulate TAM resistance. The aim of this study was to investigate the role of the miR-548as-5p/NF-κB1 axis in TAM resistance.</p> Methods and results <p>We successfully established a TAM-resistant MCF-7 (MCF-7/TamR) breast cancer cell line and calculated its TAM resistance index. The expression levels of miR-548as-5p and NF-κB1 in MCF-7/TamR cells were analyzed. By regulating the expression levels of miR-548as-5p and NF-κB1, the apoptosis rate and TAM resistance of MCF-7/TamR cells were analyzed in vivo and in vitro. The expression level of miR-548as-5p was considerable decreased, whereas that of NF-κB1 was markedly increased in the MCF-7/TamR cell line. The knockdown of miR-548as-5p in MCF-7/TamR cells decreased apoptosis following TAM treatment, whereas overexpression increased apoptosis. Reduced expression of miR-548as-5p increased NF-κB1 expression, thereby enhancing the resistance to TAM. Overexpression of miR-548as-5p partially restored TAM sensitivity and markedly increased apoptosis of MCF-7/TamR cells, whereas additional overexpression of NF-κB1 reversed these effects. These results were validated in vivo using a mouse model.</p> Conclusions <p>The miR-548as-5p/NF-κB1 axis may represent a novel therapeutic target for reducing TAM resistance in breast cancer.</p>