title: Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94127, USA.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.affiliation: Department of Medicine, Division of Oncology and Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Curtis
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
authors.forename: Shenda
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Heiser
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, 02215, USA.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Korkola
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94127, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Bayani
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, CB2 0XZ, UK.
authors.forename: Shamith
authors.initials: S
authors.lastname: Samarajiwa
authors.affiliation: Department of Medicine, Division of Oncology and Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Seoane
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dane
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Esch
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Feiler
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wang
authors.affiliation: GlaxoSmithKline, Collegeville, PA, 19425, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Hardwicke
authors.affiliation: GlaxoSmithKline, Collegeville, PA, 19425, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Laquerre
authors.affiliation: GlaxoSmithKline, Collegeville, PA, 19425, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Jackson
authors.affiliation: Cytokinetics, Inc., South San Francisco, CA, 94080, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: W Wood
authors.affiliation: GlaxoSmithKline, Collegeville, PA, 19425, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Weber
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.affiliation: Molecular Oncology, BC Cancer Research Centre, Vancouver, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: GlaxoSmithKline, Collegeville, PA, 19425, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Wooster
authors.affiliation: Cancer Research UK, Cambridge Institute, Cambridge, UK. carlos.caldas@cancer.org.uk.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA. Grayjo@ohsu.edu.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
mesh_terms: D064127:Aurora Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008938:Mitosis / Q000187:drug effects* / Q000235:genetics; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D054852:Small Molecule Libraries / Q000494:pharmacology; D016896:Treatment Outcome; D000097869:Polo-Like Kinase 1
chemical_list: D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D000097869:Polo-Like Kinase 1; C068688:centromere protein E
keywords: Breast cancer; Mitotic index; Novel therapeutics; Predictive biomarker