Transforming growth factor-bs (TGF-bs) are potent inhibitors of epithelial cell growth. Recently components of the TGF-b response path have been shown to be diminished or absent in a number of human malignancies, implicating loss of TGF-b function as one mechanism contributing to tumor development. However, TGF-b expression is often upregulated in advanced human cancers suggesting that the role played by the TGF-b system may be complex. We propose that TGF-bs function as """"""""conditional tumor suppressors"""""""". Since the effects of TGF-b are highly context-dependent, we have chosen to study this hypothesis in vivo in the whole animal, where all the complex contextual cues are maintained. Our approach has been to generate genetically engineered mice in which TGF-b function is experimentally compromised. To address the role of TGF-b in breast cancer, we have generated transgenic mice overexpressing antagonists of TGF-b action in the mammary gland/breast. We have shown that loss of TGF-b response causes abnormal mammary gland development and an increased susceptibility to tumorigenesis induced by chemical carcinogens. This proves that TGF-b can have tumor suppressor activity in the mammary gland. Conversely, our mouse model expressing a soluble TGF-b antagonist is protected against metastasis, showing that TGF-bs can have pro-oncogenic activities in late stage disease. We are currently improving the models and analyzing underlying mechanisms with a view to developing this antagonist for clinical use against metastasis. We are also working with mice in which components of the TGF-b signal transduction pathway have been genetically knocked out. This will allow us to determine whether the tumor suppressor and oncogenic activities of TGF-b are mediated by distinct signaling pathways. Finally, we complement the transgenic work with experiments in which we genetically modify human breast-derived cell lines representing different stages of the tumorigenic process, and assess their tumorigenicity in nude mice. A major focus will be the elucidation of molecular mechanisms underlying the observed changes in tumorigenicity, both by ad hoc analysis of candidate genes and pathways, and by global cDNA expression analysis. Results from all these experiments should give clinically useful insights into the functions of TGF-bs during tumor initiation, promotion and progression, and illuminate how the system could be most effectively manipulated in novel chemopreventive or therapeutic strategies.
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