The object of this proposal is to understand the tumor suppressor function of maspin, a novel serine protease inhibitor, and to test directly maspin as a therapeutic agent against metastasis and angiogenesis. After years of studying maspin in the in vitro cell culture system, we are finally at a stage to test the role of maspin in tumorigenesis and metastasis in the in vivo animal models. We will study the effects of gain and loss of maspin function on mouse mammary tumor progression using transgenic and knockout mouse models. These mice will be crossed with other well characterized mouse breast cancer model or challenged by chemical carcinogen to test the tumor suppressor activity of maspin. We hypothesize that overexpression of maspin should be protective against breast tumor metastasis, while loss of maspin will render mice more susceptible to tumor formation and metastasis. Mammary tumor metastasis and normal mammary development will be studied using a variety of established techniques, including histopathology, whole mount analyses, immunohistochemistry, and molecular biology. Most importantly, we will be able to test the effectiveness of maspin as a drug against mammary tumors in an animal model, hopefully in the near future it can lead us to translational studies in breast cancer patients. To the present, we have established transgenic mice overexpressing maspin in the mammary gland, and generated the maspin knockout mice. We have the access to all of the mouse strains for genetic crossing, and we have made the maspin protein for implanting and angiogenesis studies. Thus, all the necessary reagents are available for the successful completion of this proposal.
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