Transforming growth factor-bs (TGF-bs) are multifunctional growth factors that play complex roles in carcinogenesis. The prevailing hypothesis is that TGF-bs have tumor suppressor activity early in the carcinogenic process, but that in the later stages, tumor suppressor activity is lost and pro-oncogenic activities dominate. This switch is thought to be accompanied by a decrease in responsiveness of the tumor cell to TGF-b, and an increase in TGF-b ligand secretion that promotes the formation of a permissive stromal environment. Our research program uses genetically-engineered mouse and xenograft model systems to probe this dual role of TGF-bs in breast cancer, and elucidate underlying biological and molecular mechanisms. Where possible, we exploit this knowledge to develop new preventive or therapeutic modalities that target the TGF-b signaling network. ? ? Using a series of human breast-derived cell lines representing different stages of the tumorigenic process we have demonstrated that TGF-bs do indeed switch from tumor suppressor to pro-metastatic factors in the late stages of breast cancer. We are exploiting this model system to analyze the biological and molecular mechanisms that underlie the """"""""metastatic switch"""""""". Our recent work suggests a role for TGF-b in regulating cancer stem cell dynamics. To address whether neutralization of TGF-b might be a useful therapeutic approach for advanced cancer, we generated transgenic mice expressing a protein TGF-b antagonist, and showed that these mice are significantly protected against metastasis. Unexpectedly, there were essentially no adverse side effects of TGF-b antagonist treatment, so we are currently pushing this approach through further pre-clinical development. Finally, we are addressing the question of whether the tumor suppressor and pro-metastatic activities of TGF-b are mediated by distinct signaling pathways. To do this, we are working with mammary epithelial cells derived from mice in which different Smad components of the TGF-b signal transduction pathway have been genetically knocked out. We have data suggesting that the signal transduction component Smad3 may function as a modifier of metastatic efficiency. 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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