title: Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer.
abstract: BACKGROUND
  Intratumorous hypoxia triggers a broad cellular response mediated by the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1alpha concentrations increase during breast carcinogenesis, and are associated with poor prognosis. An earlier study noted two HIF-1alpha overexpression patterns: diffuse scattered throughout the tissue and confined to perinecrotic cells.
  
  
  OBJECTIVE
  To investigate the prognostic impact of these different HIF-1alpha overexpression patterns in relation to its downstream effectors carbonic anhydrase (CA) IX and glucose transporter 1 (GLUT-1).
  
  
  METHODS
  HIF-1alpha, CA IX, and GLUT-1 expression was studied by immunohistochemistry, including double staining for CA IX and HIF-1alpha. Clinical data included disease free survival, lymph node status, and tumour size.
  
  
  RESULTS
  HIF-1alpha overexpression (44% of cases) had a perinecrotic (13.5%) or diffuse staining pattern (30.5%). CA IX expression was detectable in 12.5% of breast cancers, whereas GLUT-1 expression was seen in 29%, with both showing perinecrotic membrane staining. Perinecrotic HIF-1alpha overexpression was highly associated with CA IX and GLUT-1 overexpression, and double staining for HIF-1alpha and CA IX showed strong expression in the same cells. Diffusely overexpressed HIF-1alpha was not associated with CA IX or GLUT-1 expression. Patients with diffuse HIF-1alpha staining had a significantly better prognosis than patients with perinecrotically overexpressed HIF-1alpha.
  
  
  CONCLUSIONS
  Different regulation pathways of HIF-1alpha overexpression exist in breast cancer: (1) hypoxia induced, perinecrotic HIF-1alpha overexpression with strong expression of hypoxia associated genes (CA IX and GLUT-1), which is associated with a poor prognosis; and (2) diffuse HIF-1alpha overexpression lacking major hypoxia associated downstream effects, resulting in a more favourable prognosis.
authors.affiliation: Departments of Pathology/Medical Oncology, VU University Medical Centre, 1081 HV Amsterdam, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: Vleugel
authors.forename: A E
authors.initials: AE
authors.lastname: Greijer
authors.forename: A
authors.initials: A
authors.lastname: Shvarts
authors.forename: P
authors.initials: P
authors.lastname: van der Groep
authors.forename: M
authors.initials: M
authors.lastname: van Berkel
authors.forename: Y
authors.initials: Y
authors.lastname: Aarbodem
authors.forename: H
authors.initials: H
authors.lastname: van Tinteren
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: P J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: E
authors.initials: E
authors.lastname: van der Wall
mesh_terms: D000951:Antigens, Neoplasm / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000032:analysis; D005260:Female; D051272:Glucose Transporter Type 1; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry / Q000379:methods; D009004:Monosaccharide Transport Proteins / Q000032:analysis; D009336:Necrosis; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis*; D011379:Prognosis; D016019:Survival Analysis; D014157:Transcription Factors / Q000032:analysis*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009363:Neoplasm Proteins; C495677:SLC2A1 protein, human; D014157:Transcription Factors; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases