HIF‐1α and CA IX staining in invasive breast carcinomas: Prognosis and treatment outcome

Abstract

Hypoxia stabilizes HIF-1a (Hypoxia Inducible Factor-1a), which then triggers the expression of several genes involved in many aspects of cancer progression, including metabolic adaptation, cell survival and angiogenesis. The aim of our study was to evaluate the impact of HIF-1a and CA IX (carbonic anhydrase IX) (one of its target genes) expression on prognosis and treatment outcome of patients with breast cancer. Because of the extreme O 2 -dependent instability of the protein, we first validated HIF-1a staining using xenograft tumours that were subjected to experimental conditions mimicking surgical clamping or sitting at room temperature under normoxic conditions after surgical excision but before fixation. Afterwards, the immunohistochemical staining of HIF-1a and CA IX was evaluated in 132 invasive breast carcinomas with a 10-year follow-up, and correlated to classical clinicopathological parameters and response to adjuvant therapy. No significant correlation was found between tumour size or nodal status and the expression of HIF-1a or CA IX. Statistically significant association was found between HIF-1a or CA IX staining and the grade, hormonal receptors loss and the presence of carcinoma in situ. Overexpression of HIF-1a and CA IX correlates with a poor prognosis in breast cancer. We show that HIF-1a is an independent prognostic factor for distant metastasis-free survival and disease-free survival in multivariate analysis. Furthermore, overexpression of HIF-1a or CA IX correlates with a poor outcome after conventional adjuvant therapy. CA IX is, however, a weaker prognostic and predictive factor than HIF-1a, and its association with HIF1a does not modify the survival curve neither response to therapy, compared to HIF-1a alone. ' 2007 Wiley-Liss, Inc.

High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer

“…It was also related to poorly differentiated tumours (P ¼ 0.0001), as already shown in different types of tumours (Couvelard et al, 2005;Trastour et al, 2007). These findings may reflect the existence of alternative regulatory modes of HIF-1a.…”

“…In some cancer cells, the VHL gene is mutated leading to strong upregulation of CAIX (up to 150-fold) as a consequence of constitutive HIF-1 activation (Pouyssegur et al, 2006). A relationship between CAIX tumour tissue expression, as detected by immunohistochemistry (IHC) and patient outcome has been reported in a wide variety of tumours (Bui et al, 2003;Hedley et al, 2003;Trastour et al, 2007;Choi et al, 2008;Klatte et al, 2009;Korkeila et al, 2009). Previous studies have reported the prognostic relevance of CAIX overexpression in NSCLC indicating a potential oncogenic function of CAIX (Swinson et al, 2003;Kim et al, 2004;Kon-no et al, 2006).…”

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

“…Hypoxia-inducible factor has been shown to play a major role in the angiogenesis and growth of various tumours, including breast (Leek et al, 2002), bladder (Palit et al, 2005), renal (Klatte et al, 2007), pancreatic (Shibaji et al, 2003) and cervical (Birner et al, 2000) cancers. Indeed, overexpression of, in particular, HIF-1a, has been correlated with unfavourable prognosis in a number of malignancies (Theodoropoulos et al, 2005;Maynard and Ohh, 2007;Trastour et al, 2007).…”

Hypoxia and cancer

“…The inherent problem related to the detection of HIF-α in tissue specimens is the short half-life of HIF-α not only in vivo but also when the specimen comes in contact with atmospheric oxygen during surgical removal. In fact, recent studies have established that this was not the case and make these studies reporting levels of HIF-α relevant [52]. It was shown that HIF-1α and CA IX expression correlate with poor prognosis in breast cancer [52].…”

“…In fact, recent studies have established that this was not the case and make these studies reporting levels of HIF-α relevant [52]. It was shown that HIF-1α and CA IX expression correlate with poor prognosis in breast cancer [52]. The longer half-life of the other potential marker proteins may make interpretation difficult as detection may reflect only past events.…”