RRM2 as a biomarker and therapeutic target in letrozole resistant estrogen receptor positive breast cancer

Letrozole is a first-line aromatase inhibitor for estrogen receptor-positive (ER +) breast cancer, yet resistance occurs in 20-30% of patients, significantly limiting therapeutic benefit. The absence of reliable pretreatment biomarkers remains a major barrier to precision therapy. This study aimed to identify robust prognostic biomarkers and elucidate molecular mechanisms underlying letrozole resistance through integrative bioinformatics, molecular docking, and cell-based functional assays. Weighted gene co-expression network analysis of transcriptomic datasets revealed a module strongly associated with nonresponse. From this, seven candidate genes (BUB1B, CENPU, KIF11, RRM2, NUSAP1, TRIP13, PRC1) were identified as significantly overexpressed in tumors and consistently correlated with poor survival in ER + breast cancer. Among them, RRM2 emerged as the most clinically relevant marker. Molecular docking demonstrated a potential competitive interaction between RRM2 and letrozole, implicating disruption of aromatase inhibition and DNA replication pathways in resistance, while functional assays in ER + cell lines showed that RRM2 modulates proliferation and MYC-CCND1 signaling. Validation in an independent letrozole-treated cohort confirmed the strong prognostic value of RRM2. These findings provide novel mechanistic insights into endocrine resistance and establish RRM2 as a pivotal prognostic biomarker and therapeutic target. This work offers a strong foundation for biomarker-guided strategies to optimize treatment and overcome resistance in ER + breast cancer.