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

Abstract

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.

Identification by phage display of single-domain antibody fragments specific for the ODD domain in hypoxia-inducible factor 1alpha

“…12 Furthermore, we have shown that high HIF-1a expression, 13 especially of the perinecrotic type 14 correlates with bad prognosis. This latter finding has recently been confirmed by Dales et al 15 in 745 breast cancer tissue samples. Studies on the role of HIF-1a are, however, hampered by the small range of available antibodies.…”

A signature predictive of disease outcome in breast carcinomas, identified by quantitative immunocytochemical assays

“…We analyzed several markers, such as CD105, Tie2, CD34, VEGF-R1 and -R2, CD146, [40][41][42][43][44] in frozen tissue to evaluate angiogenesis in breast cancers associated with poor prognosis. In this study on fixed tissue, only CD146 proved to be of prognostic significance when evaluated on TMAs in univariate analysis, and not in logistic regression.…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…For historical reasons, HIF-1α is the isoform that has been most extensively studied in clinical tumor materials and frequently been correlated with aggressive tumor disease, but in recent years high tumor levels of HIF-2α rather than HIF-1α have been shown to associate with negative overall survival and metastatic disease. In, for instance, breast carcinoma, earlier published data link HIF-1α, while later reports link HIF-2α to unfavorable disease (Schindl et al 2002;Bos et al 2003;Gruber et al 2004;Dales et al 2005;Generali et al 2006;Giatromanolaki et al 2006;Kronblad et al 2006;Helczynska et al 2008). Whether these contradicting observations reflect real differences in the tumor material analyzed, or can be attributed to methodological shortcomings is presently unknown.…”

“…In contrast to these findings, two reports show association between high HIF-1α protein expression and poor outcome in node-negative but not in node-positive subgroups of patients (Bos et al 2003;Generali et al 2006). In addition, significant associations between HIF-1α protein expression and outcome without subgroup divisions (Dales et al 2005) and unfavorable outcome in node-positive tumors, although restricted to T1/T2 tumors (Gruber et al 2004), have been published. There are several putative explanations as to why these reports differ in predicting outcome and range from small or poorly defined clinical material to technical explanations.…”