GENE TRAPPING TGF BETA TARGETS IN BREAST EPITHELIAL CELL

转化生长因子β（TGF-β）是一种多功能细胞因子，作为一种强大的抗有丝分裂原正常上皮细胞。 TGF-β的生长抑制作用通常在转化细胞中丧失，转化细胞然后可以产生TGF-β，其充当局部免疫抑制和血管生成因子。 因此，TGF-β早期通过维持细胞生长的正常平衡而作为肿瘤抑制因子，随后通过增加血管生成和抑制宿主对转化细胞的免疫应答而作为肿瘤促进因子。虽然已经了解了很多关于TGF-β细胞表面受体的信号如何被转导成基因表达的变化，但对TGF-β信号传导的靶点知之甚少。 很少有可能被TGF-β上调或下调的基因已经被确定，并且TGF-β调节生长所必需的关键靶点尚未完全确定。我们的长期目标是分类和鉴定正常乳腺上皮细胞中TGF-β调控的基因，并确定哪些基因对维持TGF-β控制的正常细胞稳态至关重要。 我们的假设是，转录调控的几套或几类基因将是必不可少的介导TGF-β生长抑制作用，和其他将是必不可少的转移或其他影响。 我们将在转化的非致瘤性乳腺上皮细胞中使用基因捕获策略，以确定TGF-β调节生长和致癌所必需的基因。

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.