title: Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer.
abstract: BACKGROUND
  Although human epidermal growth factor receptor 2 (HER2) positive or estrogen receptor (ER) positive breast cancers are treated with clinically validated anti-HER2 or anti-estrogen therapies, intrinsic and acquired resistance to these therapies appears in a substantial proportion of breast cancer patients and new therapies are needed. Identification of additional molecular factors, especially those characterized by aggressive behavior and poor prognosis, could prioritize interventional opportunities to improve the diagnosis and treatment of breast cancer.
  
  
  METHODS
  We compiled a collection of 4,010 breast tumor gene expression data derived from 23 datasets that have been posted on the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. We performed a genome-scale survival analysis using Cox-regression survival analyses, and validated using Kaplan-Meier Estimates survival and Cox Proportional-Hazards Regression survival analyses. We conducted a genome-scale analysis of chromosome alteration using 481 breast cancer samples obtained from The Cancer Genome Atlas (TCGA), from which combined expression and copy number data were available. We assessed the correlation between somatic copy number alterations and gene expression using analysis of variance (ANOVA).
  
  
  RESULTS
  Increased expression of each of the heat shock protein (HSP) 90 isoforms, as well as HSP transcriptional factor 1 (HSF1), was correlated with poor prognosis in different subtypes of breast cancer. High-level expression of HSP90AA1 and HSP90AB1, two cytoplasmic HSP90 isoforms, was driven by chromosome coding region amplifications and were independent factors that led to death from breast cancer among patients with triple-negative (TNBC) and HER2-/ER+ subtypes, respectively. Furthermore, amplification of HSF1 was correlated with higher HSP90AA1 and HSP90AB1 mRNA expression among the breast cancer cells without amplifications of these two genes. A collection of HSP90AA1, HSP90AB1 and HSF1 amplifications defined a subpopulation of breast cancer with up-regulated HSP90 gene expression, and up-regulated HSP90 expression independently elevated the risk of recurrence of TNBC and poor prognosis of HER2-/ER+ breast cancer.
  
  
  CONCLUSIONS
  Up-regulated HSP90 mRNA expression represents a confluence of genomic vulnerability that renders HER2 negative breast cancers more aggressive, resulting in poor prognosis. Targeting breast cancer with up-regulated HSP90 may potentially improve the effectiveness of clinical intervention in this disease.
authors.affiliation: Department of Surgery, Duke University Medical Center, Box 2606, 203 Research Drive, Durham, NC 27710, USA. q.cheng@duke.edu
authors.forename: Qing
authors.initials: Q
authors.lastname: Cheng
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chang
authors.forename: Joseph
authors.initials: J
authors.lastname: Geradts
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Neckers
authors.forename: Timothy
authors.initials: T
authors.lastname: Haystead
authors.forename: Neil L
authors.initials: NL
authors.lastname: Spector
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D053208:Kaplan-Meier Estimate; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; C000619706:HSF1 protein, human; C112969:HSP90AA1 protein, human; C493165:HSP90AB1 protein, human; C508053:ERBB2 protein, human