Integrative functional genomics analysis of sustained polyploidy phenotypes in breast cancer cells identifies an oncogenic profile for GINS2

Juha K. Rantala (Corresponding Author), Henrik Edgren, Laura Lehtinen, Maija Wolf, Kristine Kleivi, H.K. Vollan, Anna-Riina Aaltola, Petra Laasola, Sami Kilpinen, Petri Saviranta, Kristiina Iljin, Olli Kallioniemi (Corresponding Author)

    Research output: Contribution to journalArticleScientificpeer-review

    36 Citations (Scopus)

    Abstract

    Aneuploidy is among the most obvious differences between normal and cancer cells. However, mechanisms contributing to development and maintenance of aneuploid cell growth are diverse and incompletely understood. Functional genomics analyses have shown that aneuploidy in cancer cells is correlated with diffuse gene expression signatures and aneuploidy can arise by a variety of mechanisms, including cytokinesis failures, DNA endoreplication, and possibly through polyploid intermediate states. To identify molecular processes contributing to development of aneuploidy, we used a cell spot microarray technique to identify genes inducing polyploidy and/or allowing maintenance of polyploid cell growth in breast cancer cells. Of 5760 human genes screened, 177 were found to induce severe DNA content alterations on prolonged transient silencing. Association with response to DNA damage stimulus and DNA repair was found to be the most enriched cellular processes among the candidate genes. Functional validation analysis of these genes highlighted GINS2 as the highest ranking candidate inducing polyploidy, accumulation of endogenous DNA damage, and impairing cell proliferation on inhibition. The cell growth inhibition and induction of polyploidy by suppression of GINS2 was verified in a panel of breast cancer cell lines. Bioinformatic analysis of published gene expression and DNA copy number studies of clinical breast tumors suggested GINS2 to be associated with the aggressive characteristics of a subgroup of breast cancers in vivo. In addition, nuclear GINS2 protein levels distinguished actively proliferating cancer cells suggesting potential use of GINS2 staining as a biomarker of cell proliferation as well as a potential therapeutic target.
    Original languageEnglish
    Pages (from-to)877-888
    Number of pages12
    JournalNeoplasia
    Volume12
    Issue number11
    DOIs
    Publication statusPublished - 2010
    MoE publication typeA1 Journal article-refereed

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