Abstract CT308: Pre-surgical statin-treatment in a window-of-opportunity breast cancer trial: Changes in gene expression profiles
Authors: Bjarnadottir Olof , Johansson Ida , Veerla Srinivas , Jirstrom Karin , Grabau Dorthe , Hedenfalk Ingrid , Borgquist Signe 
Published: May 2015

Background

Lipophilic statins proposedly exert anti-tumoral effects in breast cancer. Previous studies have shown statin-induced decrease in proliferation and increased apoptosis. The underlying mechanisms are currently unexplored. The MAP kinase pathway is one of the most important pathways for cell proliferation and survival. Dual specific phosphatase 1 (Dusp1) acts as an inhibitor of the MAP kinase pathway.

The aim of this study was to explore statin-induced effects on global gene expression (GEX) profiles in primary breast cancer.

Study Design and Methods

The study was designed as a window-of-opportunity trial, including 50 patients with primary invasive breast cancer. Following core needle biopsies, patients were prescribed high-dose atorvastatin (80 mg/day) during two weeks prior to surgery. For the gene expression analysis, fresh frozen pre- and post treatment tumor samples were analyzed on Illumina's HumanHT-12 v4 microarrays. Significance Analysis of Microarrays (SAM) was performed using the TMEV v4.0 software to identify differentially expressed genes in paired samples before and after treatment. Genes with a q-value = 0 and fold change (FC) ≥ 1.4 were used for further analysis. The selected genes were analyzed by the transcription factor binding analysis program SMART. LitVAn (Literature Vector Analysis) was used for gene module functionality and functional annotation analysis was done using the GeneGo Pathways Software (MetaCore™).

Results

Fifty patients entered the study with forty-two patients completing all study parts. No serious adverse events were reported. After RNA extraction, 25 pre- and post-treatment tumor pairs with sufficient RNA quality and quantity were available for transcriptional analysis. Comparison of gene expression profiles in paired tumor samples revealed 407 significantly differentially expressed genes. A total of 32 genes were up-regulated, while 375 were down-regulated. Following filtration for LOC-genes and fold change ≥ 1,4, 67 genes were significantly changed; 21 of which were up-regulated and 46 down-regulated. Significantly up-regulated genes included DUSP1, RHOB1 and RGS1. Suggested biological processes were identified with LitVAn and SMART analysis. Finally, results from gene expression, LitVAn and SMART analyses were pooled together, thereby identifying statin-induced effects on the MAP-kinase pathway, including downstream events affecting apoptosis and cell proliferation.

Conclusions

Herein, we report statin-induced changes in gene expression profiles, indicating MAP-kinase pathway inhibition and pro-apoptotic events.

Citation Format: Olof Bjarnadottir, Ida Johansson, Srinivas Veerla, Karin Jirstrom, Dorthe Grabau, Ingrid Hedenfalk, Signe Borgquist. Pre-surgical statin-treatment in a window-of-opportunity breast cancer trial: Changes in gene expression profiles. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT308. doi:10.1158/1538-7445.AM2014-CT308