The present proposal will address the role of Tpl-2, cyclin D1 and touvlo in mammary oncogenesis. The Tpl-2 kinase is ubiquitously expressed. Tpl-2 induces cytoskeletal rearrangements and transformation of various cell types and influences cancer development at early stages, as well as cancer progression and metastasis at later stages. Tpl-2 has been shown to be activated by provirus insertion not only in retrovirus induced T cell lymphomas but also in MMTV-induced mammary carcinomas. Cyclin D1, the protein product of the PRAD-1 proto-oncogene, which is shown to interact with Tpl-2, is crucial to the development of the mammary epithelium in response to steroid hormones. In addition, cyclin D1 is also involved in mammary oncogenesis since amplification and/or overexpression of this molecule frequently correlates with the progression of mammary carcinomas. Recent data indicate that cyclin D1 plays an essential role in the regulation of mammary epithelial cell proliferation by potentiating transcription of estrogen receptor-regulated genes through its direct binding to the estrogen receptor. Both Tpl-2 and cyclin D1 interact with a novel ankyrin repeat protein, Touvlo. Touvlo interacts with the N-terminus of Tpl-2 and appears to regulate its kinase activity. Finally, multiple mutations, common in breast cancer also involve genes that activate the MAPK and SAPK pathways which are known to be activated by Tpl-2. Collectively these data suggest that deregulation of Tpl-2, cyclin D1 and touvlo is likely to be involved in the neoplastic transformation of mammary epithelial cells, and, therefore, in the induction and/or progression of mammary carcinomas. The proposed experiments will examine the phenotypic effects produced following expression of Tpl-2, cyclin D1 and touvlo, and their function in the transduction of mitogenic signals, in mammary epithelia, in vitro and in vivo. The obtained result will enhance our understanding of the growth regulation of normal and neoplastic mammary epithelia and may identify molecular markers for diagnosis and therapeutic intervention.
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