title: The prognostic value of temporal in vitro and in vivo derived hypoxia gene-expression signatures in breast cancer.
abstract: OBJECTIVE
  Recent data suggest that in vitro and in vivo derived hypoxia gene-expression signatures have prognostic power in breast and possibly other cancers. However, both tumour hypoxia and the biological adaptation to this stress are highly dynamic. Assessment of time-dependent gene-expression changes in response to hypoxia may thus provide additional biological insights and assist in predicting the impact of hypoxia on patient prognosis.
  
  
  METHODS
  Transcriptome profiling was performed for three cell lines derived from diverse tumour-types after hypoxic exposure at eight time-points, which include a normoxic time-point. Time-dependent sets of co-regulated genes were identified from these data. Subsequently, gene ontology (GO) and pathway analyses were performed. The prognostic power of these novel signatures was assessed in parallel with previous in vitro and in vivo derived hypoxia signatures in a large breast cancer microarray meta-dataset (n=2312).
  
  
  RESULTS
  We identified seven recurrent temporal and two general hypoxia signatures. GO and pathway analyses revealed regulation of both common and unique underlying biological processes within these signatures. None of the new or previously published in vitro signatures consisting of hypoxia-induced genes were prognostic in the large breast cancer dataset. In contrast, signatures of repressed genes, as well as the in vivo derived signatures of hypoxia-induced genes showed clear prognostic power.
  
  
  CONCLUSIONS
  Only a subset of hypoxia-induced genes in vitro demonstrates prognostic value when evaluated in a large clinical dataset. Despite clear evidence of temporal patterns of gene-expression in vitro, the subset of prognostic hypoxia regulated genes cannot be identified based on temporal pattern alone. In vivo derived signatures appear to identify the prognostic hypoxia induced genes. The prognostic value of hypoxia-repressed genes is likely a surrogate for the known importance of proliferation in breast cancer outcome.
authors.affiliation: Department of Radiation Oncology, MaastRO, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. maud.starmans@maastrichtuniversity.nl
authors.forename: Maud H W
authors.initials: MH
authors.lastname: Starmans
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Chu
authors.forename: Syed
authors.initials: S
authors.lastname: Haider
authors.forename: Francis
authors.initials: F
authors.lastname: Nguyen
authors.forename: Renaud
authors.initials: R
authors.lastname: Seigneuric
authors.forename: Michael G
authors.initials: MG
authors.lastname: Magagnin
authors.forename: Marianne
authors.initials: M
authors.lastname: Koritzinsky
authors.forename: Arek
authors.initials: A
authors.lastname: Kasprzyk
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D025341:Principal Component Analysis; D011379:Prognosis