Summary and Future Directions

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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Further Reading

Brown, J. M. (2000). Exploiting the hypoxic cancer cell: Mechanisms and therapeutic strategies. Mol. Medicine Today 6, 157-162.

Calvo, A., Yokoyama, Y., Smith, L. E., Ali, I., Shih, S.-U., Feldman, A. L., Libutti, S. K., Sundaram, R., and Green, J. E. (2002). Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin. Int. J. Cancer 101, 224-234.

Goonewardene, T. I., Sowter, H. M., and Harris, A. L. (2002). Hypoxia-induced pathways in breast cancer. Microsc. Res. Techn. 59, 41-48. Provides an up-to-date, general overview of the signaling mechanisms by which hypoxia may affect breast cancer.

Helczynska, K., Kronblad, A., Jogi, A., Nilsson, E., Beckman, S., Landberg, G., and Pahlman, S. (2003). Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ. Cancer Res. 63, 1441-1444.

Kato, T., Kameoka, S., Kimura, T., Nishikawa, T., and Kobayashi, M. (2003). The combination of angiogenesis and blood vessel invasion as a prognostic indicator in primary breast cancer. Br. J. Cancer 88, 1900-1908.

Kurz, H., Burri, P. H., and Djonov, V. G. (2003). Angiogenesis and vascular remodeling by intussusception: From form to function. News Physiol. Sci 18, 65-70. An excellent description of the basic steps and structural mechanisms involved in intussusceptive angiogenesis.

Malathy, P., Shekhar, V., Werdell, J., and Tait, L. (2000). Interaction with endothelial cells is a prerequisite for branching ductal-alveolar morphogenesis and hyperplasia of preneoplastic human breast epithelial cells: Regulation by estrogen. Cancer Res. 60, 439-449. Using a three-dimensional cell culture model, the authors begin to address how the interactions between the epithelium and endothelium affect formation of vascular networks and epithelial outgrowth.

Sacco, M. G., Soldati, S., Cato, E. M., Cattaneo, L., Pratesi, G., Scanziani, E., and Vezzoni, P. (2002). Combined effects on tumor growth and metastasis by anti-estrogenic and antiangiogenic therapies in MMTV-neu mice. Gene Ther. 9, 1338-1341.

Capsule Biography

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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