Hypoxia-Inducible Factor-1α Expression Predicts a Poor Response to Primary Chemoendocrine Therapy and Disease-Free Survival in Primary Human Breast Cancer

Abstract

Purpose: To investigate the relationship of hypoxia-inducible factor-1a (HIF-1a) tumor expression in predicting the response to epirubicin and disease-free survival (DFS) in patients with breast cancer enrolled in a single institution trial of primary anthracycline and tamoxifen therapy. Experimental Design: The expression of HIF-1a was assessed by immunohistochemistry in 187 patients with T 2-4 N 0-1 breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin + tamoxifen as primary systemic treatment. All patients postoperatively received four cycles of the four weekly i.v. CMF regimen (cyclophosphamide, methotrexate, and 5-fluorouracil). Patients with estrogen receptor (ER)-positive primary tumors also underwent 5 years of treatment with adjuvant tamoxifen. Carbonic anhydrase IX (CAIX) was also scored as a marker of HIF activity. Results: Overall response to therapy progressively decreased with increasing tumor HIF-1a (P < 0.05), and HIF-1awas an independent predictor of response (P < 0.048). HIF-1aexpression was also associated with a significantly shorter DFS (P < 0.02) in all patients and in ER-positive but not in ER-negative patients. Furthermore, CAIX positivity conferred a significantly shorter DFS (P = 0.02) compared with CAIX-negative tumors in patients with HIF-1a-negative tumors. Conclusions: HIF-1a expression in patients with breast cancer is a marker of poor therapy response and outcome, especially in ER-positive patients. The combination of two hypoxia markers has greater utility than assessing just one, and patients with hypoxia markers in their tumors may be suitable for administration of drugs that reduce HIF-1a expression and increase oxygen delivery to the tumor bed before starting neoadjuvant therapies.Tumor growth and metastasis is dependent on the generation of a neovasculature. However, newly formed vessels function poorly in supplying oxygen and nutrient requirements in many tumors. Hypoxia, the pathophysiologic consequence of the structurally and functionally disturbed microcirculation (1), is therefore a common feature in solid tumors. Tumors respond to cellular oxygen deprivation using the ubiquitous family of transcription factors known as hypoxia-inducible factors (HIF; ref. 2). Under normal oxygen tension, HIF-1a is hydroxylated by specific prolyl hydroxylases, leading to recognition and binding by the von Hippel-Lindau protein, and targeting for degradation through the proteasome. In conditions of hypoxia, molecular oxygen is not available for hydroxylase activity, which leads to HIF-1a protein stabilization and translocation to the nucleus where it binds to aryl hydrocarbon nuclear translocators resulting in the activation of several gene pathways involved in angiogenesis, glycolysis, erythropoiesis, and apoptosis (see ref.3). Overexpression of HIF-1a protein has been identified in many tumor types (4), with high levels influencing the growth rate and metastatic potential of these cancers. In breast cancers, the frequen...

BRCA1 tumours correlate with a HIF-1α phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression

“…In sporadic breast cancer, previous studies have shown that HIF-1a overexpression has a role in breast carcinogenesis and is correlated with a poor prognosis (Generali et al, 2006). However, little is known about the role of HIF-1a in hereditary breast carcinogenesis with only one report in a small series (n ¼ 30) suggesting overexpression of HIF-1a present in a higher frequency in BRCA1-related cancers than sporadic cancers (van der Groep et al, 2008).…”

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

“…However, there are early reports correlating high HIF-1α protein expression with shorter overall and disease-free survival time in patients with lymph node-positive breast cancer, whereas this association was not significant in lymph-node negative patients (Schindl et al 2002;Kronblad et al 2006). 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.…”

“…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.…”

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

“…Both HIF-1 α and HIF-2 α are widely overexpressed in many human cancers and are frequently associated with malignancy and a poor prognosis (Birner et al , 2000 ;Aebersold et al , 2001 ). Furthermore, high HIF-1 α protein levels have been shown to correlate with incomplete responses to chemotherapy and radiotherapy (Aebersold et al , 2001 ;Koukourakis et al , 2002 ;Bachtiary et al , 2003 ;Generali et al , 2006 ). Hypoxia per se affects radiation sensitivity as the radiation-induced DNA damage is dependent on oxygen (Gray et al , 1953 ).…”