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

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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.