title: Global Transcriptional Changes Following Statin Treatment in Breast Cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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/).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  We report potential statin-induced changes in global tumor gene expression profiles, indicating MAPK pathway inhibition and proapoptotic events.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Olöf
authors.initials: O
authors.lastname: Bjarnadottir
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Siker
authors.initials: S
authors.lastname: Kimbung
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Ida
authors.initials: I
authors.lastname: Johansson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. SciBlu genomics, Lund University, Sweden.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Veerla
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Jönsson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Grabau
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hedenfalk
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. Department of Oncology, Skåne University Hospital, Lund, Sweden. signe.borgquist@med.lu.se.
authors.forename: Signe
authors.initials: S
authors.lastname: Borgquist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000069059:Atorvastatin / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D046228:Microarray Analysis; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome / Q000235:genetics*
chemical_list: D009363:Neoplasm Proteins; D000069059:Atorvastatin; D020929:Mitogen-Activated Protein Kinase Kinases