Abstract
Statins purportedly exert antitumoral effects, but the underlying mechanisms are currently not fully elucidated. The aim of this study was to explore potential statin-induced effects on global gene expression profiles in primary breast cancer. This window-of-opportunity phase II trial enrolled 50 newly diagnosed breast cancer patients prescribed atorvastatin (80 mg/day) for 2 weeks presurgically. Pre- and posttreatment tumor samples were analyzed using Significance Analysis of Microarrays (SAM) to identify differentially expressed genes. Similarly, SAM and gene ontology analyses were applied to gene expression data derived from atorvastatin-treated breast cancer cell lines (MCF7, BT474, SKBR3, and MDAMB231) comparing treated and untreated cells. The Systematic Motif Analysis Retrieval Tool (SMART) was used to identify enriched transcription factor-binding sites. Literature Vector Analysis (LitVAn) identified gene module functionality, and pathway analysis was performed using GeneGo Pathways Software (MetaCore; https://portal.genego.com/). Comparative analysis of gene expression profiles in paired clinical samples revealed 407 significantly differentially expressed genes (FDR = 0); 32 upregulated and 375 downregulated genes. Restricted filtration (fold change ≥1.49) resulted in 21 upregulated and 46 downregulated genes. Significantly upregulated genes included DUSP1, RHOB1, GADD45B, and RGS1. Pooled results from gene ontology, LitVAn and SMART analyses identified statin-induced effects on the apoptotic and MAPK pathways among others. Comparative analyses of gene expression profiles in breast cancer cell lines showed significant upregulation of the mevalonate and proapoptotic pathways following atorvastatin treatment. We report potential statin-induced changes in global tumor gene expression profiles, indicating MAPK pathway inhibition and proapoptotic events.
Highlights
Statins are generally prescribed as cholesterol-lowering agents for patients with cardiovascular disease and hypercholesterolemia
Pooled results from gene ontology, Literature Vector Analysis (LitVAn) and Systematic Motif Analysis Retrieval Tool (SMART) analyses identified statin-induced effects on the apoptotic and MAPK pathways among others
This study demonstrates highly significant changes in the expression of genes related to the MAPK pathway and apoptosis, suggesting statin-induced cancer-inhibitory effects
Summary
Statins are generally prescribed as cholesterol-lowering agents for patients with cardiovascular disease and hypercholesterolemia. Statins act by reducing de novo cholesterol synthesis through the inhibition of 3-hydroxy-3-metylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway [1]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The aim of this study was to explore potential statininduced effects on global gene expression profiles in primary breast cancer. Preand posttreatment tumor samples were analyzed using Significance Analysis of Microarrays (SAM) to identify differentially expressed genes. SAM and gene ontology analyses were applied to gene expression data derived from atorvastatintreated breast cancer cell lines (MCF7, BT474, SKBR3, and MDAMB231) comparing treated and untreated cells. Literature Vector Analysis (LitVAn) identified gene module functionality, and pathway analysis was performed using GeneGo Pathways Software (MetaCore; https://portal.genego.com/)
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