Integrative Functional Genomics Analysis of Sustained Polyploidy Phenotypes in Breast Cancer Cells Identifies an Oncogenic Profile for GINS2
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 wi...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2010-11-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558610800363 |
| _version_ | 1818808740268212224 |
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| author | Juha K. Rantala Henrik Edgren Laura Lehtinen Maija Wolf Kristine Kleivi Hans Kristian Moen Vollan Anna-Riina Aaltola Petra Laasola Sami Kilpinen Petri Saviranta Kristiina Iljin Olli Kallioniemi |
| author_facet | Juha K. Rantala Henrik Edgren Laura Lehtinen Maija Wolf Kristine Kleivi Hans Kristian Moen Vollan Anna-Riina Aaltola Petra Laasola Sami Kilpinen Petri Saviranta Kristiina Iljin Olli Kallioniemi |
| author_sort | Juha K. Rantala |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T19:46:22Z |
| format | Article |
| id | doaj.art-6f6d90d7e02a40de9e1ca47441b9ead5 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-18T19:46:22Z |
| publishDate | 2010-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-6f6d90d7e02a40de9e1ca47441b9ead52022-12-21T20:55:18ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022010-11-01121187788810.1593/neo.10548Integrative Functional Genomics Analysis of Sustained Polyploidy Phenotypes in Breast Cancer Cells Identifies an Oncogenic Profile for GINS2Juha K. Rantala0Henrik Edgren1Laura Lehtinen2Maija Wolf3Kristine Kleivi4Hans Kristian Moen Vollan5Anna-Riina Aaltola6Petra Laasola7Sami Kilpinen8Petri Saviranta9Kristiina Iljin10Olli Kallioniemi11Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, FinlandInstitute for Molecular Medicine Finland (FIMM), Biomedicum 2U, University of Helsinki, Helsinki, FinlandMedical Biotechnology, VTT Technical Research Centre of Finland, Turku, FinlandInstitute for Molecular Medicine Finland (FIMM), Biomedicum 2U, University of Helsinki, Helsinki, FinlandMedical Biotechnology, VTT Technical Research Centre of Finland, Turku, FinlandDepartment of Genetics, Institute for Cancer Research, Oslo University Hospital - Radiumhospitalet, Oslo, NorwayMedical Biotechnology, VTT Technical Research Centre of Finland, Turku, FinlandMedical Biotechnology, VTT Technical Research Centre of Finland, Turku, FinlandInstitute for Molecular Medicine Finland (FIMM), Biomedicum 2U, University of Helsinki, Helsinki, FinlandMedical Biotechnology, VTT Technical Research Centre of Finland, Turku, FinlandMedical Biotechnology, VTT Technical Research Centre of Finland, Turku, FinlandMedical Biotechnology, VTT Technical Research Centre of Finland, Turku, FinlandAneuploidy 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.http://www.sciencedirect.com/science/article/pii/S1476558610800363 |
| spellingShingle | Juha K. Rantala Henrik Edgren Laura Lehtinen Maija Wolf Kristine Kleivi Hans Kristian Moen Vollan Anna-Riina Aaltola Petra Laasola Sami Kilpinen Petri Saviranta Kristiina Iljin Olli Kallioniemi Integrative Functional Genomics Analysis of Sustained Polyploidy Phenotypes in Breast Cancer Cells Identifies an Oncogenic Profile for GINS2 Neoplasia: An International Journal for Oncology Research |
| title | Integrative Functional Genomics Analysis of Sustained Polyploidy Phenotypes in Breast Cancer Cells Identifies an Oncogenic Profile for GINS2 |
| title_full | Integrative Functional Genomics Analysis of Sustained Polyploidy Phenotypes in Breast Cancer Cells Identifies an Oncogenic Profile for GINS2 |
| title_fullStr | Integrative Functional Genomics Analysis of Sustained Polyploidy Phenotypes in Breast Cancer Cells Identifies an Oncogenic Profile for GINS2 |
| title_full_unstemmed | Integrative Functional Genomics Analysis of Sustained Polyploidy Phenotypes in Breast Cancer Cells Identifies an Oncogenic Profile for GINS2 |
| title_short | Integrative Functional Genomics Analysis of Sustained Polyploidy Phenotypes in Breast Cancer Cells Identifies an Oncogenic Profile for GINS2 |
| title_sort | integrative functional genomics analysis of sustained polyploidy phenotypes in breast cancer cells identifies an oncogenic profile for gins2 |
| url | http://www.sciencedirect.com/science/article/pii/S1476558610800363 |
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