title: In silico discovery of mitosis regulation networks associated with early distant metastases in estrogen receptor positive breast cancers.
abstract: The aim of this study was to perform comparative analysis of multiple public datasets of gene expression in order to identify common genes as potential prognostic biomarkers. Additionally, the study sought to identify biological processes and pathways that are most significantly associated with early distant metastases (<5 years) in women with estrogen receptor-positive (ER+) breast tumors. Datasets from three published studies were selected for in silico analysis of gene expression profiles of ER+ breast cancer, using time to distant metastasis as the clinical endpoint. A subset of 44 differently expressed genes (DEGs) was found common to all three studies and characterized by mitotic checkpoint genes and pathways that regulate mitotic spindle and chromosome dynamics. DEG promoter regions were enriched with NFY binding sites. Analysis of miRNA target sites identified significant enrichment of miR-192, miR-193B, and miR-16-1 targets. Aberrant mitotic regulation could drive increased genomic instability leading to a progression towards an early onset metastatic phenotype. The relative importance of mitotic instability may reflect the clinical utility of mitotic poisons in metastatic breast cancer, including poisons such as the taxanes, epothilones, and vinca alkaloids.
authors.affiliation: Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Gusev
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Riggins
authors.forename: Krithika
authors.initials: K
authors.lastname: Bhuvaneshwar
authors.forename: Robinder
authors.initials: R
authors.lastname: Gauba
authors.forename: Laura
authors.initials: L
authors.lastname: Sheahan
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: Subha
authors.initials: S
authors.lastname: Madhavan
keywords: early distant metastasis; estrogen receptor alpha-positive; microRNA targets; mitotic checkpoint signaling; mitotic regulation network