Reversal of tamoxifen resistance by artemisinin in ER plus breast cancer: bioinformatics analysis and experimental validation

Breast cancer is the leading cause of cancer-related deaths in women worldwide, with Hormone Receptor (HR)+ being the predominant subtype. Tamoxifen (TAM) serves as the primary treatment for HR+ breast cancer. However, drug resistance often leads to recurrence, underscoring the need to develop new therapies to enhance patient quality of life and reduce recurrence rates. Artemisinin (ART) has demonstrated ef fi cacy in inhibiting the growth of drug-resistant cells, positioning art as a viable option for counteracting endocrine resistance. This study explored the interaction between artemisinin and tamoxifen through a combined approach of bioinformatics analysis and experimental validation. Five characterized genes ( ar, cdkn1a, erbb2, esr1, hsp90aa1 ) and seven drug-disease crossover genes ( cyp2e1, rorc, mapk10, glp1r, egfr, pgr, mgll ) were identi fi ed using WGCNA crossover analysis. Subsequent functional enrichment analyses were conducted. Our fi ndings con fi rm a signi fi cant correlation between key cluster gene expression and immune cell in fi ltration in tamoxifen-resistant and-sensitized patients. scRNA-seq analysis revealed high expression of key cluster genes in epithelial cells, suggesting artemisinin ' s speci fi c impact on tumor cells in estrogen receptor (ER)-positive BC tissues. Molecular target docking and in vitro experiments with artemisinin on LCC9 cells demonstrated a reversal effect in reducing migratory and drug resistance of drug-resistant cells by modulating relevant drug resistance genes. These results indicate that artemisinin could potentially reverse tamoxifen resistance in ER-positive breast cancer.