Overexpression of hypoxia-inducible factor HIF-1α predicts early relapse in breast cancer : a retrospective study in a series of 745 patients.

488 HIF-1 is a heterodimeric transcriptional activator composed of HIF-1α and HIF-1β subunits, which are basic helix-loop-helix-PAS domain proteins. HIF-1 is involved in tumour growth and metastasis by regulating genes involved in response to hypoxia. The biological activity of HIF-1 is determined by the expression and activity of the HIF-1α subunit which is mainly regulated by oxygen-dependant posttranslational modifications. Moreover, HIF-1α expression seems to be regulated at least in part by mRNA alternative splicing. HIF-1α overexpression has been shown in a variety of human cancers, but only few studies have documented the prognostic relevance of HIF-1α protein expression in breast cancer. The aim of our study was to determine accurately the impact of HIF-1α 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-1α expression was investigated using immunohistochemical assays on frozen sections. HIF-1α protein expression was correlated with patients’ outcome (median follow-up, 13.5 years) and with HIF-1α isoforms expression evaluated by real-time quantitative PCR method. Univariate (Kaplan-Meier) analysis showed that high levels of HIF-1α protein expression (cutoff = 10%) significantly correlated with poor overall survival (p=0.019). HIF-1α expression correlated with high metastasis risk among the whole group of patients (p=0.008). Multivariate analysis (Cox model) revealed that the HIF-1α predictive value was independent of other current prognostic indicators. Moreover among node negative ones, HIF-1α protein expression was also significantly predictive of metastasis risk (p=0.03) and of relapse (p=0.035). Correlation between HIF-1α protein detection and expression of HIF-1α splice variants in tumors is also discussed. These data suggest that HIF-1α is associated with a worse prognosis in patients with invasive breast carcinoma.