Transforming growth factor beta (TGF-beta) is a multifunctional cytokine that acts as a powerful anti-mitogen for normal epithelial cells. Growth inhibition by TGF-beta is often lost in transformed cells, which can then produce TGF-beta which acts as a local immunosuppressive and angiogenic factor. Thus, TGF-beta acts early as a tumor suppressor by maintaining a normal balance of cell growth, and later as a tumor promoter by increasing angiogenesis and suppressing host immune responses to transformed cells. Although much has been learned about how signals from TGF-beta cell surface receptors are transduced into changes in gene expression, little is known about the targets of TGF-beta signaling. Few of the genes likely to be up or down regulated by TGF-beta have been identified, and the critical targets necessary for regulation of growth by TGF-beta have not been fully defined. Our long term goal is to catalogue and identify the genes regulated by TGF-beta in normal breast epithelial cells, and to determine which of those genes is essential for maintenance of normal cellular homeostasis controlled by TGF-beta. Our hyposthesis is that transcriptional regulation of a few sets or classes of genes will be essential to mediating TGF-beta growth inhibitory effects, and that others will be essential for metastasis or other effects. We will use a gene trapping strategy in transformed, non-tumorigenic breast epithelial cells in order to identify those genes essential for TGF-beta regulation of growth and carcinogenesis.
