Global Transcriptional Changes Following Statin Treatment in Breast Cancer

O. Bjarnadottir, S. Kimbung, I. Johansson, S. Veerla, M. Jonsson, P.-O. Bendahl, D. Grabau, I. Hedenfalk, S. Borgquist
2015 Clinical Cancer Research  
Statins induce changes in gene expression in breast cancer 2 120-150 words statement of translational relevance Statins are per-oral drugs normally prescribed as cholesterol-lowering agents. Studies have shown cholesterol-independent pleiotropic effects related to cancer development. Statins purportedly exert anti-tumoral effects on breast cancer cells by decreasing proliferation and increasing apoptosis, supported by data on the protein level. However, less is known about the mechanisms of
more » ... on at the transcriptional level. In this window-of-opportunity trial, 50 patients with primary invasive breast cancer were prescribed atorvastatin (80 mg/day) for two weeks pre-surgically. Global gene expression profiling was performed on the pre-and posttreatment tumor sample pairs. This study demonstrates highly significant changes in the expression of genes related to the MAP-kinase pathway and apoptosis, suggesting statininduced cancer-inhibitory effects. The results were confirmed in vitro in breast cancer cell lines. Future phase III breast cancer trials are needed to address the potential role of statins as anti-cancer drugs in addition to current treatment guidelines. Abstract Background Statins purportedly exert anti-tumoral 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. Study Design and Methods This window-of-opportunity phase II trial enrolled 50 newly diagnosed breast cancer patients prescribed atorvastatin (80 mg/day) for two weeks pre-surgically. Pre-and post-treatment 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-bindingsites. Literature Vector Analysis (LitVAn) identified gene module functionality, and pathway analysis was performed using GeneGo Pathways Software (MetaCore™) (https://portal.genego.com/). Results Comparative analysis of gene expression profiles in paired clinical samples revealed 407 significantly differentially expressed genes (FDR=0); 32 up-regulated and 375 downregulated genes. Restricted filtration (fold change ≥1.49) resulted in 21 up-regulated and 46 down-regulated genes. Significantly up-regulated genes included DUSP1, RHOB1, GADD45B and RGS1. Pooled results from gene ontology, LitVAn and SMART analyses identified statin-induced effects on the apoptotic and Mitogen-activated phosphatase kinase pathway (MAPK) pathways among others. Comparative analyses of gene expression profiles Research. on May 1, 2017.
doi:10.1158/1078-0432.ccr-14-1403 pmid:25840970 fatcat:eqs22mqhe5dmhbprdsdnhmhzvi