Levels of Hypoxia-Inducible Factor-1  During Breast Carcinogenesis

Abstract

The level of HIF-1 alpha increases as the pathologic stage increases and is higher in poorly differentiated lesions than in the corresponding type of well-differentiated lesions. Increased levels of HIF-1 alpha are associated with increased proliferation and increased expression of ER and VEGF. Thus, increased levels of HIF-1 alpha are potentially associated with more aggressive tumors.

Levels of hypoxia‐inducible factor‐1α independently predict prognosis in patients with lymph node negative breast carcinoma

“…It has been shown that high microvessel density, VEGF overexpression, and increased lactate production are associated with a poor prognosis in human malignancies. 13,14,36 Similar to the results from our previous study, 19 we found that high levels of HIF-1␣ were correlated with overexpression of VEGF, one of its main downstream effectors, confirming angiogenesis as one of the proposed mechanisms by which HIF-1 activation stimulates tumor growth and metastasis.…”

“…No studies measuring O 2 tension in breast carcinoma in relation to patient survival have been published; however, in patients with cervical carcinoma, it is known that in vivo intratumoral hypoxia predicts poor survival. 1 In the current study and in our previous report, 19 HIF-1␣ staining often was observed in viable cells surrounding areas of necrosis, suggesting that hypoxia contributes to HIF-1␣ up-regulation in breast carcinoma. Adaptation to hypoxia is mediated by HIF-1, which stimulates angiogenesis (through VEGF) and high and anaerobic metabolism (through glucose transporters and glycolytic enzymes).…”

“…This confirmed our hypothesis, based on the knowledge that the presence of hypoxia in a tumor reflects a poor prognosis, 1 that increased levels of HIF-1␣ occur especially in patients with poorly differentiated breast lesions. 19 Subgroup analysis showed that this could be explained completely by the group of lymph-node negative patients, as in lymph-node positive patients, levels of HIF-2 were not predictive. This finding suggests that levels of HIF-1␣ may be used to select highrisk patients with negative lymph node status who would benefit from systemic adjuvant therapy.…”

“…After deparaffinization and rehydration, the Catalyzed Signal Amplification System (DAKO, Glostrup, Denmark) was used for detecting HIF-1␣, as described previously. 19,34 Briefly, target retrieval solution (DAKO) was used for antigen retrieval with all slides placed in a water bath for 45 minutes at 97°C. A cooling off period of 20 minutes preceded the incubation of the anti-HIF-1␣ mouse monoclonal H1␣ 67 at a dilution of 1:500 (Abcam, Cambridge, United Kingdom).…”

“…Recently, we found increased levels of HIF-1␣ during breast carcinogenesis, especially in poorly differentiated lesions. 19 In addition, it has been reported that levels of carbonic anhydrase IX, a downstream product of HIF-1, harbors prognostic potential in human breast carcinoma. 20 Thus, multiple mechanisms point to HIF-1 as a key regulator of tumor survival and progression in breast carcinoma.…”