Contribution of Hypoxia-Inducible Factor (HIF)-1a to Normal Mammary Gland Development and Mammary Tumorigenesis

摘要

During pregnancy the mammary epithelium and it 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)-l complex, HIF-1, was deleted in the murine mammary gland using the Cre/ioxP system. Although vascular density was similar, loss of HIF-l (impaired mammary differentiation and lipid metabolism) culminating in lactation failure (Objective No. 1). HIF-l over-expression has been reported in breast tumors. Therefore, we next deleted the von Hippel Lindau (vHL) gene, which results in constitutive over-expression of HIF-l in order to determine if HIF-l over-expression directly contributes to mammary tumorigenesis (Objective No. 2). These studies have demonstrated that VHL is an important mediator of normal alveolar outgrowth and survival during pregnancy and lactation. However, neither deletion of vHL, nor the corresponding increased expression of HiF-iCin the mammary epithelium, is sufficient to induce breast tumorigenesis. Observation of wild type or VHL deleted mice crossed to the MMTV-neu breast model is in progress, but no tumors have been observed to date in mice of either genotype. In conclusion, mammary gland development and epithelial cell function depend on the tightly regulated balance of HIF-1(and VHL function).