ORIGINAL ARTICLE

Differential prognostic impact of hypoxia induced and diffuse HIF-1 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 and E van der Wall⁵

¹ Departments of Pathology/Medical Oncology, VU University Medical Centre, 1081 HV Amsterdam, The Netherlands
² Department of Pathology, University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands
³ The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
⁴ Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK
⁵ Division of Internal Medicine and Dermatology, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands

Correspondence to:
Correspondence to:
Professor P J van Diest
Department of Pathology, University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands; P.J.vanDiest{at}lab.azu.nl

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

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

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

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

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

Abbreviations: 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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