In the previous funding period of this grant, we focused on the role of hypoxic response and the hypoxia-responsive transcription factor HIF-1alpha in tumorigenesis. In this renewal, we propose to now concentrate on one specific tissue, the mammary gland, and the requirement for this response in tumorigenic expansion and vascularization. Work from our laboratory in the previous funding period has established that HIF-1alpha expression is required for mouse embryonic development, and is involved in the vascularization and growth of tumors derived from HIF-1alpha null cells. Recently HIF-1alpha protein has been demonstrated to be up-regulated in a variety of human solid tumors, in particular breast tumors that exhibit high rates of proliferation. Hypothesis: Hypoxic response, via HIF-1alpha, is a critical aspect of physiological adaptation during the rapid proliferation and de-differentiation of mammary epithelial cells during tumorigenesis. Objectives/Aims: To determine the role of hypoxic response: 1) In mammary epithelial transformation and tumor formation induced by chemical carcinogens, and in transgenic mouse models of breast cancer. 2) In expansion and metabolic adaptation to hypoxia of transformed mammary epithelium. 3) In neo-vascularization of mammary tumors. In order to test the hypothesis that hypoxic response through HIF-1 is critically important for mammary tumorigenesis, we have specifically removed from the mammary epithelium two proteins that regulate the hypoxic response: 1) HIF1-alpha and 2) the protein that interacts with and targets HIF-1alpha protein for ubiquitination under normoxic conditions, the von Hippel-Lindau (VHL) factor. In both cases, this has been done through the use of conditionally targeted mouse strains. We have recently characterized normal mammary gland development in each of these models, and both animals, i.e., those lacking HIF-1alpha or VHL in mammary epithelium, exhibit striking defects in mammary gland development and lactation. Since HIF-1alpha overexpression has been reported in breast tumors, the goals of this proposal are to determine if deletion of either HIF-1alpha or VHL, which results in HIF-1alpha overexpression, affects transformation, expansion and neo-vascularization of the murine mammary gland in transgenic breast tumor models, or in mice treated with the chemical carcinogen DMBA. We anticipate that the work carried out in this proposal will aid greatly in evaluating the potential for targeting hypoxia-response in breast cancer.
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