Hypoxia-Inducible Factor-1α in carcinogenesis and progression of breast cancer

Abstract

This thesis is primarily focused on the previously hardly explored role of HIF-1 in breast cancer. HIF-1 is a transcription factor induced by hypoxia, but also by some oncogenes, tumor suppressor genes and growth factors. Activated HIF-1 can induce angiogenesis, glycolysis, erythropoiesis, and other processes allowing cells to survive during hypoxia or hypoglycaemia. These processes are also involved in the development of breast cancer and subsequent formation of metastases. Thus, HIF-1 could be suspected to play an important role in breast cancer. If so, HIF-1 would be a potential therapeutic target because of its broad regulatory impact. We therefore tried to unravel the role of HIF-1 in breast carcinogenesis, its interaction with cell cycle proteins, growth factors and steroid receptors. In addition, we determined the role of HIF-1 as a prognosticator. From a clinical point of view, we tried to answer the question why different breast cancer patients show such a broad variety in 18FDG (radioactively labeled glucose analogue) signal intensity as measured by positron emission tomography (PET). We composed a model with most important determinants of quantitative glucose metabolism in breast cancer, assuming a role of HIF-1 in the variable uptake of 18FDG. Further, we hypothesized that the cell cycle regulating protein BCL-6 is not only involved in lymphomas, but might also be present in breast cancer. In fact, our data not only showed the presence of BCL-6 in breast cancer, but, also an association of BCL-6 with HIF-1. Conclusions 1. Different stages of human breast carcinogenesis were studied for expression of HIF-1α. We noted the overexpression of HIF-1α in precursor lesions (ductal carcinoma in situ) as well as in invasive cancer specimens. In contrast, we did not detect increased levels of HIF-1α in tissue specimens of normal breast nor in areas with ductal hyperplasia. 2. Both cellular hypoxia and oncogenes are considered main activators of HIF-1 activity in breast cancer, with a minor role for immune modulators. Unraveling whether hypoxia, oncogenes or growth factors are responsible for HIF-1 activation will identify potential therapeutic targets. In the present thesis, we link both HER-2/neu, EGFR and PDGF with HIF-1 activation. 3. Blocking HIF-1 seems to be attractive in breast cancer treatment since several downstream effects of HIF-1 (such as VEGF production, formation of angiogenesis, and stimulation of glycolysis) all potentiate aggressiveness of breast cancer. 4. As a consequence, levels of HIF-1α represent tumor aggressiveness and predict prognosis. This is especially valuable to identify high risk lymph node negative breast cancer patients, and might be used for further studies to assess the risk of pure DCIS recurrence. 5. BCL-6 protein is overexpressed in breast cancer, possibly due to gene amplification, and is associated with p53, cyclin D1 and HIF-1α. 6. The different intensity of FDG-PET scanning between breast cancer patients can be explained by a biologic model of glucose transport and rate of proliferation per tumor volume