RRM2 as a Key Biomarker and Therapeutic Target in Letrozole-Resistant ER+ Breast Cancer: Insights from Bioinformatics and Molecular Docking

Letrozole is a first-line aromatase inhibitor for estrogen receptor-positive (ER+) breast cancer; however, resistance develops in 20–30% of patients, limiting therapeutic efficacy. The inability to predict treatment response before therapy initiation remains a significant challenge, as no reliable biomarkers have been established. This study aimed to identify novel prognostic biomarkers and elucidate the molecular mechanisms underlying letrozole resistance using integrative bioinformatics and molecular docking approaches. Through weighted gene coexpression network analysis, a gene module highly associated with letrozole nonresponse was identified. Seven candidate genes—BUB1B, CENPU, KIF11, RRM2, NUSAP1, TRIP13, and PRC1—were significantly overexpressed in tumors and strongly correlated with poor survival in ER + breast cancer. Among them, RRM2 emerged as the most significant prognostic marker. Molecular docking analysis demonstrated that letrozole binds to RRM2, suggesting a potential competitive interaction with aromatase that may contribute to resistance. Validation in an independent letrozole-treated cohort confirmed RRM2’s strong prognostic value. These findings provide new insights into the molecular mechanisms driving letrozole resistance and identify RRM2 as both a prognostic biomarker and a potential therapeutic target. This study advances the understanding of endocrine resistance and offers promising avenues for biomarker-driven treatment strategies in ER + breast cancer.