Cyclins operating in the G1 phase (G1 cyclins) are the ultimate recipients of all oncogenic pathways. One of the major challenges is to decipher how various oncogenic pathways are connected to the core cell cycle machinery. There is growing evidence, including our own work, that this wiring is different in various cell types. The goal of this proposal is to elucidate how oncogenic pathways signal to the core cell cycle machinery in mammary epithelial cells. In the past, we crossed mice lacking one of the G1 cyclins, cyclin D1, with breast cancer-prone mice expressing activated oncogenes in their mammary epithelium. We found that cyclin D1-/- mice are resistant to breast cancers triggered by the Ras and Neu (ErbB-2). Our analyses revealed that in mammary epithelial cells, the Neu->Ras pathway impacts the core cell cycle machinery through cyclin D1. Importantly, cyclin D1-deficient mice remain fully sensitive to mammary carcinomas driven by the Myc and Wnt-1 oncogenes, indicating that these two oncogenes signal through other (currently unknown) targets. In the work proposed in this application we will follow up on these observations and we will address the following questions: (a) Is the continued presence of cyclin D1 required for the maintenance of Neu- driven oncogenic proliferation? We will test this hypothesis in the work described in the Specific Aim 1. (b) What are the cell cycle targets for Myc and Wnt-1 in mammary epithelial cells? While we found that cyclin D1-deficient mice remain fully susceptible to mammary carcinomas triggered by the Wnt-1 and c-Myc, our analyses allowed us to identify some candidate cell cycle targets for these oncogenes. We will test these hypotheses in the studies described in the Specific Aim 2. (c) Is the Neu->Ras pathway connected to the cell cycle machinery in human mammary epithelial cells also via cyclin D1, or it signals through other targets? Studies described in Specific Aim 3 will address this issue.
The Specific Aims Are: 1. To test whether the continued presence of cyclin D1 is required for proliferation of mammary carcinomas triggered by the Neu oncogene. 2. To determine how the Wnt-1 and Myc oncogenes are connected to the cell cycle machinery in mouse mammary epithelial cells. 3. To determine how the Neu->Ras pathway signals to the cell cycle machinery in human mammary epithelial cells. ? ? ? ? ? ?
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