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Differential prognostic impact of hypoxia induced and diffuse HIF-1α expression in invasive breast cancer
  1. M M Vleugel1,
  2. A E Greijer1,
  3. A Shvarts2,
  4. P van der Groep2,
  5. M van Berkel1,
  6. Y Aarbodem1,
  7. H van Tinteren3,
  8. A L Harris4,
  9. P J van Diest2,
  10. E van der Wall5
  1. 1Departments of Pathology/Medical Oncology, VU University Medical Centre, 1081 HV Amsterdam, The Netherlands
  2. 2Department of Pathology, University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands
  3. 3The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
  4. 4Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK
  5. 5Division of Internal Medicine and Dermatology, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands
  1. Correspondence to:
 Professor P J van Diest
 Department of Pathology, University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands;


Background: Intratumorous hypoxia triggers a broad cellular response mediated by the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1α concentrations increase during breast carcinogenesis, and are associated with poor prognosis. An earlier study noted two HIF-1α overexpression patterns: diffuse scattered throughout the tissue and confined to perinecrotic cells.

Aims: To investigate the prognostic impact of these different HIF-1α overexpression patterns in relation to its downstream effectors carbonic anhydrase (CA) IX and glucose transporter 1 (GLUT-1).

Methods: HIF-1α, CA IX, and GLUT-1 expression was studied by immunohistochemistry, including double staining for CA IX and HIF-1α. Clinical data included disease free survival, lymph node status, and tumour size.

Results: HIF-1α 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-1α overexpression was highly associated with CA IX and GLUT-1 overexpression, and double staining for HIF-1α and CA IX showed strong expression in the same cells. Diffusely overexpressed HIF-1α was not associated with CA IX or GLUT-1 expression. Patients with diffuse HIF-1α staining had a significantly better prognosis than patients with perinecrotically overexpressed HIF-1α.

Conclusions: Different regulation pathways of HIF-1α overexpression exist in breast cancer: (1) hypoxia induced, perinecrotic HIF-1α overexpression with strong expression of hypoxia associated genes (CA IX and GLUT-1), which is associated with a poor prognosis; and (2) diffuse HIF-1α overexpression lacking major hypoxia associated downstream effects, resulting in a more favourable prognosis.

  • CA IX, carbonic anhydrase IX
  • DFS, disease free survival
  • GLUT-1, glucose transporter 1
  • HIF-1, hypoxia inducible factor 1
  • HRE, hypoxia response element
  • VEGF, vascular endothelial growth factor

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