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Differential prognostic impact of hypoxia induced and diffuse HIF-1α expression in invasive breast cancer

By M.M. Vleugel, A.E. Greijer, A. Shvarts, P. van der Groep, M. van Berkel, Y. Aarbodem, H. van Tinteren, A.L. Harris, P.J. van Diest and E. van der Wall


Background: Intratumorous hypoxia triggers a broad cellular response mediated by the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1a concentrations increase during breast carcinogenesis,\ud and are associated with poor prognosis. An earlier study noted two HIF-1a overexpression patterns: diffuse scattered throughout the tissue and confined to perinecrotic cells. Aims: To investigate the prognostic impact of these different HIF-1a overexpression patterns in relation to\ud its downstream effectors carbonic anhydrase (CA) IX and glucose transporter 1 (GLUT-1).\ud Methods: HIF-1a, CA IX, and GLUT-1 expression was studied by immunohistochemistry, including double\ud staining for CA IX and HIF-1a. Clinical data included disease free survival, lymph node status, and tumour size. Results: HIF-1a 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-1a overexpression was highly associated with CA IX and GLUT-1 overexpression, and double staining for HIF-1a and CA IX showed strong expression in the same cells. Diffusely overexpressed HIF-1a was not associated with CA IX or GLUT-1 expression. Patients with diffuse HIF-1a staining had a significantly better prognosis than patients with perinecrotically overexpressed HIF-1a.\ud Conclusions: Different regulation pathways of HIF-1a overexpression exist in breast cancer: (1) hypoxia induced, perinecrotic HIF-1a overexpression with strong expression of hypoxia associated genes (CA IX and GLUT-1), which is associated with a poor prognosis; and (2) diffuse HIF-1a overexpression lacking major hypoxia associated downstream effects, resulting in a more favourable prognosis

Topics: Geneeskunde
Year: 2005
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