| The role of hypoxia-inducible factor-1α (HIF-1α ) is under increasing scrutiny by cancer researchers. HIF-1α binds the consensus sequence 5'-RCGTG-3' (where R is any purine) in the hypoxia-response elements of various target genes. HIF-1α activates the transcription of many genes controlling glucose transporters, glycolytic enzymes, gluconeogenesis, high-energy phosphate metabolism, growth factors, erythropoiesis, heme metabolism, iron transport, vasomotor regulation, and nitric oxide synthesis and, thus, may increase the survival of tumor cells under hypoxic conditions. Hypoxia influences the proliferation of tumor cells, the rate of apoptotic cell death, and metastasis. In addition, by activating transcription of the vascular endothelial growth factor (VEGF) gene, HIF-1α is considered to be a central initiator of angiogenic activity in tumors.The level of HIF-1α in cells is dependent on the intracellular oxygen concentration. When cells have normal concentrations of oxygen, HIF-1α protein is continuously degraded via the ubiquitin pathway. However, under low concentrations of oxygen (hypoxic conditions), the ubiquitination of HIF-1α is blocked, the protein is stabilized, and thus the intracellular level of the protein is increased. Although the exact mechanism of oxygen sensing remains to be elucidated, the cell probably senses its oxygen concentration through reactive oxygen species, so that stabilization of the HIF-1α protein is said to be redox induced.A nuclear localization signal at the C-terminal end of HIF-1α allows its transport from the cytoplasm to the nucleus, where it forms an active HIF-1 complex by binding to HIF-1β . HIF-1 β can form heterodimers with other proteins, such as the aryl hydrocarbon receptor, and is constitutively and abundantly present. Thus, the amount of HIF-1α protein in the nucleus is rate limiting and determines the functional activity of the HIF-1 Acomplex.The level of the HIF-1α protein is inversely related to the oxygen tension in cultured cells and in vivo. Hypoxic oxygen tensions that induce HIF-1α levels have been demonstrated in tumors in vivo and are associated with a poor clinical outcome. HIF-1α activity also is associated with tumor progression and angiogenesis in xenograft assays. These observations and the facts that increased levels of HIF-1α are found in many common human cancers suggest that HIF-1α has an important role in cancer progression.Since the discovery of HIF-1, the characteristics of HIF-1α have been explored in many studies using cultured cell lines. In this study, we focused on the role of HIF-1α in the progression and metastases of human breast cancers. Because angiogenesis is necessary for hyperplastic epithelial cells to progress to malignant cells and because HIF-1α may induce angiogenesis by activating transcription of the VEGF gene, we propose that HIF-1α plays a role in the progression and metastases of human breast careers. We tested this hypothesis by evaluating the levels of HIF-1α in mammary adenosis tissue and in breast invasive ductal cancer and by determining whether the level of HIF-1α expression was associated with the expression of VEGF. MATERIALS AND METHODSThe level of HIF-1α was examined in randomly selected samples of breast tissue from patients. These samples had been collected from the pathology department of the Second Affiliated Hospital College of Medical Science Zhejang University. Specimens of invasive carcinoma and mammary adenosis tissue were obtained from excision biopsy procedures or mastectomies. None of the patients with invasive breast cancer had received any preoperative therapy. All specimens were fixed in neutral 4% buffered formaldehyde. We examined mammary adenosis tissue (from 10 patients) and invasive ductal carcinoma (from 86 patients) by two pathologists. Grading of invasive cancer was done according to the procedure of Elston and Ellis. The two respective grading observers were blinded in scoring all slides for HIF-1 α staining with respect to VEGF. Immunohistochemistry.The expressi... |
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