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

28 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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Polyploidy
Genomics
Aneuploidy
Breast Neoplasms
Phenotype
Genes
DNA Damage
DNA
Growth
Maintenance
Endoreduplication
Cell Proliferation
Neoplasms
Cytokinesis
Nuclear Proteins
Computational Biology
Transcriptome
DNA Repair
Biomarkers
Staining and Labeling

Cite this

Rantala, J. K., Edgren, H., Lehtinen, L., Wolf, M., Kleivi, K., Vollan, H. K., ... Kallioniemi, O. (2010). Integrative functional genomics analysis of sustained polyploidy phenotypes in breast cancer cells identifies an oncogenic profile for GINS2. Neoplasia, 12(11), 877-888. https://doi.org/10.1593/neo.10548
Rantala, Juha K. ; Edgren, Henrik ; Lehtinen, Laura ; Wolf, Maija ; Kleivi, Kristine ; Vollan, H.K. ; Aaltola, Anna-Riina ; Laasola, Petra ; Kilpinen, Sami ; Saviranta, Petri ; Iljin, Kristiina ; Kallioniemi, Olli. / Integrative functional genomics analysis of sustained polyploidy phenotypes in breast cancer cells identifies an oncogenic profile for GINS2. In: Neoplasia. 2010 ; Vol. 12, No. 11. pp. 877-888.
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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.",
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Rantala, JK, Edgren, H, Lehtinen, L, Wolf, M, Kleivi, K, Vollan, HK, Aaltola, A-R, Laasola, P, Kilpinen, S, Saviranta, P, Iljin, K & Kallioniemi, O 2010, 'Integrative functional genomics analysis of sustained polyploidy phenotypes in breast cancer cells identifies an oncogenic profile for GINS2', Neoplasia, vol. 12, no. 11, pp. 877-888. https://doi.org/10.1593/neo.10548

Integrative functional genomics analysis of sustained polyploidy phenotypes in breast cancer cells identifies an oncogenic profile for GINS2. / Rantala, Juha K. (Corresponding Author); Edgren, Henrik; Lehtinen, Laura; Wolf, Maija; Kleivi, Kristine; Vollan, H.K.; Aaltola, Anna-Riina; Laasola, Petra; Kilpinen, Sami; Saviranta, Petri; Iljin, Kristiina; Kallioniemi, Olli (Corresponding Author).

In: Neoplasia, Vol. 12, No. 11, 2010, p. 877-888.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - Integrative functional genomics analysis of sustained polyploidy phenotypes in breast cancer cells identifies an oncogenic profile for GINS2

AU - Rantala, Juha K.

AU - Edgren, Henrik

AU - Lehtinen, Laura

AU - Wolf, Maija

AU - Kleivi, Kristine

AU - Vollan, H.K.

AU - Aaltola, Anna-Riina

AU - Laasola, Petra

AU - Kilpinen, Sami

AU - Saviranta, Petri

AU - Iljin, Kristiina

AU - Kallioniemi, Olli

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.1593/neo.10548

DO - 10.1593/neo.10548

M3 - Article

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SP - 877

EP - 888

JO - Neoplasia

JF - Neoplasia

SN - 1522-8002

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