Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. Department of Oncology, Skåne University Hospital, Lund, Sweden.
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
Clin Cancer Res. 2015 Aug 1;21(15):3402-11. doi: 10.1158/1078-0432.CCR-14-1403. Epub 2015 Apr 3.
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.
他汀类药物据称具有抗肿瘤作用，但目前其潜在机制尚未完全阐明。本研究旨在探索他汀类药物对原发性乳腺癌患者肿瘤全局基因表达谱的潜在影响。
本研究为前瞻性Ⅱ期临床试验，共纳入 50 例新诊断为乳腺癌的患者，这些患者在术前 2 周内每天服用阿托伐他汀（80mg）。采用差异表达基因分析（SAM）分析治疗前后肿瘤样本，以识别差异表达的基因。同样，采用 SAM 和基因本体论分析方法对阿托伐他汀处理的乳腺癌细胞系（MCF7、BT474、SKBR3 和 MDAMB231）的基因表达数据进行分析，比较处理和未处理的细胞。采用系统 motif 分析检索工具（SMART）识别富集的转录因子结合位点。文献向量分析（LitVAn）识别基因模块功能，采用 GeneGo 通路软件（MetaCore；https://portal.genego.com/）进行通路分析。
配对临床样本基因表达谱的比较分析显示，有 407 个基因差异表达显著（FDR = 0）；其中 32 个上调，375 个下调。限制过滤（倍数变化≥1.49）得到 21 个上调和 46 个下调基因。明显上调的基因包括 DUSP1、RHOB1、GADD45B 和 RGS1。基因本体论、LitVAn 和 SMART 分析的综合结果表明，他汀类药物诱导的作用包括凋亡和 MAPK 等通路。乳腺癌细胞系基因表达谱的比较分析显示，阿托伐他汀治疗后甲羟戊酸和促凋亡途径显著上调。
我们报告了他汀类药物对肿瘤全局基因表达谱的潜在影响，表明 MAPK 途径抑制和促凋亡事件。
