In this revised application, the investigators have designed experiments to investigate the biological effects of two functions of tTG. First, Balb-c 3T3 fibroblasts and human breast cancer cells will be transfected with tTG and tTG mutants and the role of tTG overexpression on cell proliferation will be investigated by flow cytometry. Second, the effect of tTG overexpression from stromal fibroblasts on the growth and metastasis of human breast cancer cells will be investigated. Finally, the role of tTG in the epithelium will be determined by the overexpression of tTG in transgenic mice. Targeting the expression of tTG to the mammary epithelium using the MMTV promoter will make it possible to examine the influence of tTG on the normal process of mammary gland development, lactation and the subsequent involuton of the gland post-lactation. Finally, to determine the influence of tTG on breast cancer cell growth and development in an in vivo model of human breast cancer, MMTV/tTG transgenic mice will be mated with transgenic mice that express the activated neu-oncogene and the rate of tumor growth and development will be assessed. Knowledge concerning the physiology and the pathophysiology of tTG in normal and malignant mammary epithelial cells may lead to novel strategies in the treatment of breast cancer.
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