title: Integrative functional genomics analysis of sustained polyploidy phenotypes in breast cancer cells identifies an oncogenic profile for GINS2.
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.
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland.
authors.forename: Juha K
authors.initials: JK
authors.lastname: Rantala
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.forename: Laura
authors.initials: L
authors.lastname: Lehtinen
authors.forename: Maija
authors.initials: M
authors.lastname: Wolf
authors.forename: Kristine
authors.initials: K
authors.lastname: Kleivi
authors.forename: Hans Kristian Moen
authors.initials: HK
authors.lastname: Vollan
authors.forename: Anna-Riina
authors.initials: AR
authors.lastname: Aaltola
authors.forename: Petra
authors.initials: P
authors.lastname: Laasola
authors.forename: Sami
authors.initials: S
authors.lastname: Kilpinen
authors.forename: Petri
authors.initials: P
authors.lastname: Saviranta
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D006801:Humans; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D011123:Polyploidy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C556406:GINS2 protein, human; D011518:Proto-Oncogene Proteins