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The role of hypoxia inducible factor-1[alpha] in mammary gland tumorigenesis

Abstract

Maintenance of oxygen homeostasis is crucial at both the cellular and systemic level in mammals. In poorly oxygenated (hypoxic) microenvironments adaptation to hypoxia involves changes in gene expression crucial for cell and tissue viability, known as the hypoxic response. The master regulator of the hypoxic response is the transcription factor Hypoxia Inducible Factor (HIF)- 1[alpha]. Deregulation of HIF-1[alpha] activity has been shown to contribute to various pathologies including cancer. The aim of this dissertation is to elucidate the role of the hypoxic response, and the contribution of HIF- 1[alpha], during mammary gland tumor progression and metastasis. The first chapter provides a brief overview of the hypoxic response and regulation of hypoxic gene expression by HIF-1[alpha]. A brief overview of normal mouse mammary gland development is discussed. Lastly, an introduction to the Polyoma Middle T (PyMT) transgenic mouse model of breast cancer used in these studies is provided. The second chapter describes the results of conditional deletion of HIF-1[alpha] in the tumor mammary epithelial cells (MECs) in the PyMT mouse model. Loss of HIF-1alpha resulted in delayed tumor onset due to reduced tumor cell proliferation. Loss of HIF-1[alpha] also resulted in significantly increased survival and reduced pulmonary metastasis. These findings demonstrated that the transcriptional activity of HIF-1[alpha] is a significant regulator of tumor progression and metastatic potential. The third chapter presents the regulation of E-cadherin expression by HIF-1[alpha]. Through Cre-mediated excision of the HIF-1[alpha] and VHL gene in tumor MECs, we demonstrate that E-cadherin is not transcriptionally regulated by HIF-1[alpha]. Instead, we show that HIF- 1[alpha] activity promotes the internalization of E- cadherin protein through a VEGF/VEGFR1 autocrine signaling pathway during hypoxia stress. The concluding chapter describes the initial results and future direction of continuing work to elucidate the contribution of HIF- 1[alpha] mediated cell-autonomous changes versus changes in the tumor microenvironment during mammary gland tumor progression and metastasis

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