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dc.contributor.authorHu, Zhi
dc.contributor.authorMao, Jian-Hua
dc.contributor.authorCurtis, Christina
dc.contributor.authorHuang, Ge
dc.contributor.authorGu, Shenda
dc.contributor.authorHeiser, Laura
dc.contributor.authorLenburg, Marc E
dc.contributor.authorKorkola, James E
dc.contributor.authorBayani, Nora
dc.contributor.authorSamarajiwa, Shamith
dc.contributor.authorSeoane, Jose A
dc.contributor.authorDane, Mark A
dc.contributor.authorEsch, Amanda
dc.contributor.authorFeiler, Heidi S
dc.contributor.authorWang, Nicholas J
dc.contributor.authorHardwicke, Mary Ann
dc.contributor.authorLaquerre, Sylvie
dc.contributor.authorJackson, Jeff
dc.contributor.authorW Wood, Kenneth
dc.contributor.authorWeber, Barbara
dc.contributor.authorSpellman, Paul T
dc.contributor.authorAparicio, Samuel
dc.contributor.authorWooster, Richard
dc.contributor.authorCaldas, Carlos
dc.contributor.authorGray, Joe W
dc.description.abstractBACKGROUND: High mitotic activity is associated with the genesis and progression of many cancers. Small molecule inhibitors of mitotic apparatus proteins are now being developed and evaluated clinically as anticancer agents. With clinical trials of several of these experimental compounds underway, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that carry molecular aberrations that confer high mitotic activity, and to develop molecular markers that distinguish which tumors will be most responsive to mitotic apparatus inhibitors. METHODS: We identified a coordinately regulated mitotic apparatus network by analyzing gene expression profiles for 53 malignant and non-malignant human breast cancer cell lines and two separate primary breast tumor datasets. We defined the mitotic network activity index (MNAI) as the sum of the transcriptional levels of the 54 coordinately regulated mitotic apparatus genes. The effect of those genes on cell growth was evaluated by small interfering RNA (siRNA). RESULTS: High MNAI was enriched in basal-like breast tumors and was associated with reduced survival duration and preferential sensitivity to inhibitors of the mitotic apparatus proteins, polo-like kinase, centromere associated protein E and aurora kinase designated GSK462364, GSK923295 and GSK1070916, respectively. Co-amplification of regions of chromosomes 8q24, 10p15-p12, 12p13, and 17q24-q25 was associated with the transcriptional upregulation of this network of 54 mitotic apparatus genes, and we identify transcription factors that localize to these regions and putatively regulate mitotic activity. Knockdown of the mitotic network by siRNA identified 22 genes that might be considered as additional therapeutic targets for this clinically relevant patient subgroup. CONCLUSIONS: We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.subjectCell Line, Tumor
dc.subjectBreast Neoplasms
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectCell Cycle Proteins
dc.subjectProto-Oncogene Proteins
dc.subjectChromosomal Proteins, Non-Histone
dc.subjectTreatment Outcome
dc.subjectGene Expression Profiling
dc.subjectCell Proliferation
dc.subjectGene Amplification
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectRNA Interference
dc.subjectGenome, Human
dc.subjectGene Regulatory Networks
dc.subjectSmall Molecule Libraries
dc.subjectKaplan-Meier Estimate
dc.subjectAurora Kinases
dc.titleGenome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer.
prism.publicationNameBreast Cancer Res
dc.contributor.orcidSamarajiwa, Shamith [0000-0003-1046-0601]
dc.contributor.orcidCaldas, Carlos [0000-0003-3547-1489]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMRC (MR/N501876/1)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idCancer Research UK (CB4140)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (C507/A16278)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (60098573)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (unknown)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
pubs.funder-project-idMRC (MR/N501876/1)
pubs.funder-project-idMRC (MC_UU_12022/10)

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International