Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer.
Vleugel MM., Greijer AE., Shvarts A., van der Groep P., van Berkel M., Aarbodem Y., van Tinteren H., Harris AL., van Diest PJ., van der Wall E.
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. AIMS: 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.