Differential prognostic impact of hypoxia induced and diffuse HIF-1α expression in invasive breast cancer
- M M Vleugel1,
- A E Greijer1,
- A Shvarts2,
- P van der Groep2,
- M van Berkel1,
- Y Aarbodem1,
- H van Tinteren3,
- A L Harris4,
- P J van Diest2,
- E van der Wall5
- 1Departments of Pathology/Medical Oncology, VU University Medical Centre, 1081 HV Amsterdam, The Netherlands
- 2Department of Pathology, University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands
- 3The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- 4Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK
- 5Division of Internal Medicine and Dermatology, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands
- Correspondence to: Professor P J van Diest Department of Pathology, University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands; P.J.vanDiestlab.azu.nl
- Accepted 24 June 2004
Abstract
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
