title: Integrative analysis of cyclin protein levels identifies cyclin b1 as a classifier and predictor of outcomes in breast cancer.
abstract: OBJECTIVE
  We studied the expression levels of cyclins B1, D1, and E1 and the implications of cyclin overexpression for patient outcomes in distinct breast cancer subtypes defined by clinical variables and transcriptional profiling.
  
  
  METHODS
  The expression levels of cyclins B1, D1, and E1 were quantified in 779 breast tumors and 53 cell lines using reverse phase protein arrays and/or transcriptional profiling.
  
  
  RESULTS
  Whereas cyclin E1 overexpression was a specific marker of triple-negative and basal-like tumors, cyclin B1 overexpression occurred in poor prognosis hormone receptor-positive, luminal B and basal-like breast cancers. Cyclin D1 overexpression occurred in luminal and normal-like cancers. Breast cancer subgroups defined by integrated expression of cyclins B1, D1, and E1 correlated significantly (P < 0.000001) with tumor subtypes defined by transcriptional profiling and clinical criteria. Across three hormone receptor-positive data sets, cyclin B1 was the dominant cyclin associated with poor prognosis in univariate and multivariate analyses. Although CCNE1 was present in significantly higher copy numbers in basal-like versus other subtypes (ANOVA P < 0.001), CCNB1 gene copy number did not show gain in breast cancer. Instead, cyclin B1 expression was increased in tumors with co-occurrence of TP53 mutations and MYC amplification, a combination that seems to characterize basal-like and luminal B tumors. CCNB1 gene expression was significantly correlated with PLK, CENPE, and AURKB gene expression.
  
  
  CONCLUSIONS
  Cyclins B1, D1, and E1 have distinct expressions in different breast cancer subtypes. Novel PLK, CENPE, and AURKB inhibitors should be assessed for therapeutic utility in poor prognosis cyclin B1-overexpressing breast cancers.
authors.affiliation: The University of Texas M. D. Anderson Cancer Center (MDACC), Houston, Texas, USA.
authors.forename: Roshan
authors.initials: R
authors.lastname: Agarwal
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.forename: Simen
authors.initials: S
authors.lastname: Myhre
authors.forename: Mark
authors.initials: M
authors.lastname: Carey
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
authors.forename: Jan
authors.initials: J
authors.lastname: Alsner
authors.forename: Katherine
authors.initials: K
authors.lastname: Stemke-Hale
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.forename: Richard M
authors.initials: RM
authors.lastname: Neve
authors.forename: Wen Lin
authors.initials: WL
authors.lastname: Kuo
authors.forename: Therese
authors.initials: T
authors.lastname: Sorlie
authors.forename: Aysegul
authors.initials: A
authors.lastname: Sahin
authors.forename: Vicente
authors.initials: V
authors.lastname: Valero
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Borresen-Dale
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
mesh_terms: D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019926:Cyclin B / Q000235:genetics* / Q000378:metabolism; D056744:Cyclin B1; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods / Q000706:statistics & numerical data; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D040901:Proteomics / Q000379:methods / Q000706:statistics & numerical data; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016019:Survival Analysis
chemical_list: C534699:CCNB1 protein, human; C475820:CCNE1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D019927:Cyclin E; D015513:Oncogene Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human