Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?

Abstract

Intratumoral hypoxia has been shown to be a prognostic parameter in diverse studies [1]. Electrode measurements of oxygen tension have thus far served as the gold standard for its determination. The disadvantage of this method is its inability to discriminate between different cell types and areas of different cell viability [2].Hypoxia-inducible factor 1 is a heterodimeric DNA-binding complex, of which the β subunit is responsible for its translocation into the nucleus and the α subunit for its oxygen sensitivity. Under normoxic conditions the hypoxia-inducible factor 1 alpha (hif-1α) protein is degraded within minutes, whereas under hypoxic conditions it is stabilized and upregulated [3]. hif-1α is a transcription factor for target genes, involved in cell adaptation to stress parameters such as hypoxia. These genes are involved mainly in the modulation of erythropoesis, angiogenesis and metabolism.A spatial coexpression of hif-1α and the nitroimidazole EF5, the levels of which are selectively lowered only in viable hypoxic cells, was recently reported [4]. Further-DFS = disease-free survival; DMFS = distant metastasis-free survival; 5-FU = 5-fluorouracil; hif-1α = hypoxia-inducible factor 1 alpha; OS = overall survival. AbstractBackground: Hypoxia-inducible factor 1 alpha (hif-1α) furnishes tumor cells with the means of adapting to stress parameters like tumor hypoxia and promotes critical steps in tumor progression and aggressiveness. We investigated the role of hif-1α expression in patients with node-positive breast cancer.

Angiogenesis and hypoxia in lymph node metastases is predicted by the angiogenesis and hypoxia in the primary tumour in patients with breast cancer

“…Existing breast cancer literature is not always straightforward on associations between clinico-pathological data and angiogenesis and hypoxia. Some authors indeed find the same associations (Hansen et al, 2000;Chia et al, 2001;Bos et al, 2003;Koukourakis et al, 2003;Giatromanolaki et al, 2004;Gruber et al, 2004), whereas others do not (Fox et al, 1994;Costello et al, 1995;Aranda and Laforga, 1996;Schindl et al, 2002;Blackwell et al, 2004). Differences in study population and in the methodology of .…”

Hypoxia inducible factor‐1α is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response

“…HIF-1a has also been implicated as an independent prognostic marker in both lymph node-negative 26 as well as lymph node-positive breast cancers. 27,28 Also, high histological grade, ER and PR (progesterone receptor) negativity and the presence of necrotic regions have been linked to the presence of HIF-1a, 29 but the relation between histological grade, ER status and HIF-1a expression differs between reports. 14,26,27 This difference could potentially be explained by the fact that the role of HIF-1a as a prognostic marker was investigated in small cohorts of pre-and postmenopausal patients with both early and advanced breast cancer, receiving different forms of treatment.…”

“…In the whole material, 24% of the tumours showed nuclear HIF-1a staining, which is in concordance with other articles even if the patient cohorts differ between the reported studies. 27,28,34 ER downregulation in breast cancer cell lines as well as in primary breast cancer has been linked to HIF-1a induction. 14,19,20,26 In contrast, ER positivity has also been reported to be associated with HIF-1a expression, 18 whereas others have not observed any significant link between HIF-1a and ER expression.…”

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.…”