title: Subcellular FIH-1 expression patterns in invasive breast cancer in relation to HIF-1α expression.
abstract: BACKGROUND
  Hypoxia Inducible Factor-1α (HIF-1α) expression in breast cancer is associated with a poor clinical outcome. HIF-1α shows two expression patterns: the canonical poor prognosis hypoxia-related perinecrotic pattern and a diffuse expression pattern that seems to have less downstream effects and is clearly associated with poor survival. Factor-inhibiting hypoxia-inducible factor 1 (FIH-1) inhibits HIF-1 activity by hydroxylating the C-terminal trans-activation domain of the HIF-1α subunit, thus preventing HIF-1 from recruiting co-activators CPB/p300, which are important for inducing the transcription of target genes. The aim of this study was to investigate the expression patterns of FIH-1 in breast cancer and evaluate the relationship between FIH-1 and HIF-1α expression in breast cancer as a possible explanation for apparently less downstream effects of diffuse HIF-1α expression.
  
  
  METHODS
  Tissue sections from 92 consecutive invasive breast carcinomas were stained by immunohistochemistry for FIH-1, HIF-1α, glucose transporter 1 (GLUT-1) and carbonic anhydrase IX (CAIX).
  
  
  RESULTS
  45 cases overexpressed HIF-1α, 5 of which in a perinecrotic fashion while FIH-1 was positive in 73 of the 92 cases studied. Contrary to our expectations, three out of five cases with perinecrotic HIF-1α expression were also positive for FIH1. Cytoplasmic FIH-1 correlated with HIF-1α expression (P = 0.03) and tumor grade (P = 0.01). HIF-1α overexpression predicted poorer prognosis as usual (P = 0.02). FIH expression had no additional prognostic value to HIF-1α.
  
  
  CONCLUSIONS
  FIH1 is expressed in the majority of invasive breast carcinomas and shows distinct subcellular localization patterns. FIH-1 expression does not seem to explain the proposed functional differences between diffuse and perinecrotic HIF-1α expression in breast cancer.
authors: Department of Pathology, University Medical Centre Utrecht, The Netherlands.
authors: Agon
authors: A
authors: Hyseni
authors: Petra
authors: P
authors: van der Groep
authors: Elsken
authors: E
authors: van der Wall
authors: Paul J
authors: PJ
authors: van Diest
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human