Effect of simvastatin on gene expression varies across breast cancer cell subtypes

Abstract Background: Simvastatin has attracted interest for its potential anticancer effects, yet its molecular impact may vary among breast cancer models. We investigated its effects on genes involved in cell-cycle control, tumour progression, and immune regulation in three breast cancer cell lines. Methods and Results: MCF-7, SK-BR-3, and MDA-MB-231 cells were exposed to simvastatin for 24 hours. Cellular metabolic activity was assessed using XTT. Based on concentration–response profiles, gene expression was examined after treatment with 50 µM simvastatin in MDA-MB-231 cells and 75 µM in MCF-7 and SK-BR-3 cells. Seven target genes were analysed by quantitative real-time PCR. TCGA-BRCA and TIMER3 data provided additional context. Simvastatin reduced metabolic activity at higher concentrations, with differences among cell lines. CDKN1A expression increased significantly in all three models. CXCR4 and PD-L1 expression decreased significantly in MDA-MB-231 cells, whereas PTEN expression increased in SK-BR-3 cells while CD44, MAPK14, and NOTCH1 showed no significant changes. Public datasets revealed variation in selected gene expression between breast tumours and normal tissue and across molecular subtypes. Conclusion: CDKN1A upregulation was shared across the three models, while other transcriptional responses differed by cell line. These findings suggest that cellular background influences the molecular response to simvastatin and warrant validation in additional models and at the protein and functional levels.