Hypoxia-inducible factor-1a (HIF-1a) is a transcription factor that is involved in tumour growth and metastasis by regulating genes involved in response to hypoxia. HIF-1a protein overexpression has been shown in a variety of human cancers, but only 2 studies have documented the prognostic relevance of HIF-1a expression in breast cancer. The aim of our study was to determine accurately the impact of HIF-1a expression on prognosis in a large series (n = 745) of unselected patients with invasive breast cancer in terms of overall survival, local recurrence and distant metastasis risk. HIF-1a expression was investigated using immunohistochemical assays on frozen sections, and correlated with patients' outcome (median follow-up = 13.5 years). Univariate (Kaplan-Meier) analysis showed that high levels of HIF-1a expression (cutoff = 10%) significantly correlated with poor overall survival ( p = 0.019). HIF-1a expression correlated with high metastasis risk among the whole group of patients ( p = 0.008). Multivariate analysis (Cox model) showed that the HIF-1a predictive value was independent of other current prognostic indicators. Moreover among node negative ones, HIF-1a expression was also significantly predictive of metastasis risk ( p = 0.03) and of relapse (p = 0.035). All the data suggest that HIF-1a is associated with a worse prognosis in patients with invasive breast carcinoma. Furthermore HIF-1a immunodetection may be considered as a potential indicator for selecting patients who could benefit from specific therapies interfering with HIF-1a pathway. ' 2005 Wiley-Liss, Inc.

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