In order to better develop targeted therapies so that they are specific for breast tumors, it is critical to know how the vasculature develops in the normal breast and how it becomes altered to induce hypoxia during breast tumorigen-esis. Further studies that seek to determine the localization and timing of expression of angiogenic factors and their regulators/receptors in the epithelium, endothelium, myoepithelium, and stroma should begin to clarify the important mediators of mammary gland angiogenesis. With the widespread availability of well-described, tissue-specific conditional gene deletion and tumor mouse models, the genetic tools are now available to begin comparing the effects of deletion of each putative angiogenic factor in the mammary epithelium or the endothelium. The ultimate goal is to be able to distinguish how these two cell types interact with each other in normal development as well as during mammary tumorigenesis.
Cre/loxP conditional gene deletion: A gene deletion strategy in which a portion of a gene, flanked by bacteriophage P1 recombination target sites (loxP sites), will be deleted upon introduction of the Cre recombi-nase protein. In our case, the HIF-1a conditional mouse created in our laboratory was bred to a transgenic mouse expressing Cre under control of the MMTV promoter (MMTV-Cre, Jackson Labs), which targets Cre expression preferentially to the mammary epithelium.
Ductal carcinoma in situ (DCIS): The most common early lesion observed in breast cancer in which the epithelial cells have proliferated beyond the normal single layer of epithelium, but not have not yet penetrated the integrity of the basement membrane. The analogous structure in the mouse is referred to as the hyperplastic alveolar nodule or HAN.
Ovariectomy: A surgical procedure to remove both ovaries from female mice in order to deplete circulating levels of steroid hormones responsible for initiating alveolar development.
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Tiffany N. Seagroves is currently investigating the contribution of the hypoxia response during normal mammary gland development and mammary tumorigenesis in the laboratory of Randall S. Johnson. This work was supported by a fellowship to T. N. S. from the Department of Defense Breast Cancer Research Program (DAMD17-01-1-0186) and NIH grand CA82515 to R. S. J.
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