The Contribution of Hypoxia-Inducible Factor (HIF) -1 Alpha to Normal Mammary Gland Development and Mammary Tumorigenesis
Annual summary rept. 1 Oct 2002-30 Sep 2003
CALIFORNIA UNIV SAN DIEGO LA JOLLA
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During pregnancy the mammary epithelium and its supporting vasculature rapidly expand to prepare for lactation. To investigate the role of oxygenation and metabolism in these processes the oxygen-responsive component of the hypoxia-inducible factor HIF-1 complex, HIF-1 alpha, was deleted in the murine mammary gland using the CreloxP system. Although vascular density remained similar, loss of HIF-1 alpha impaired mammary differentiation and lipid metabolism, culminating in lactation failure and changes in milk composition Objectives 1 . Next, we investigated the effects of deletion of the von Hipple Lindau VHL gene in the mammary gland, in order to stimulate constitutive over-expression of HIF-1 alpha the mammary epithelium, to determine if HIF-1 alpha contributes to mammary gland tumorigenesis Revised Objective 2. Preliminary results from this work indicate that VHL is also an important mediator of normal mammary gland differentiation, confirming that regulation of the hypoxic response is critical for normal mammary gland development. The ultimate goal is of these experiments is to determine the role of HIF-1 alpha over-expression during mammary gland tumorigenesis.
- Medicine and Medical Research