Signaling transduction pathways and networks have recently proven to be attractive targets for cancer therapy. Gleevac, herceptin (TM), C225, Irressa, and CCI779 have all induced remarkable, non-toxic responses in a subset of patients where abnormalities in the appropriate signaling pathway are present, respectively, bcrabl (Gleevac), ErbB-2 (also known as HER-2/neu, herceptin(TM)), EGFR (C225 and Irressa), and the PI-3K pathway (CCI779). The development and utilization of novel molecular therapeutics requires a detailed understanding of the signaling aberrations present in tumors. This program project grant (PPG) aims at understanding signaling pathways of a few key molecules that play critical roles in breast tumor progression. The immediate goals of this PPG are to characterize the ErbB-2/PI-3K/Akt signaling transduction pathways or """"""""network of nodes"""""""" in the initiation and progression of breast cancer through understanding these signaling pathways in details, and their contributions to development of breast cancer. This PPG consists of four interactive projects supported by one administrative core. Each of the four projects has its own unique set of specific aims that target at the common theme and are interdependent on components of other projects in the PPG. Project 1 focuses on the role of Akt-mediatefl signaling and its contribution to the cell growth and tumor progression in breast cancer cells. Project 1 will evaluate two critical snbstrates of Akt, namely, p21 cip1/WAF1and MDM2. Project 2 plans to exploit two well-characterized transgenic mouse models expressing either mutant PyV mT de-coupled from the PI-3K pathway or activated erbB-2 in themammary epithelium. Project 3 will test the hypothesis that the p85 regulatory subunit of PI-3K plays a critical role in the regulation of breast cancer initiation and progression through its ability to recruit Racl, Pakl and other interacting molecules. Project 4 will investigate GJM deregulation and antiapoptosis by ErbB-2 in breast cancer cells. The hypothesis to be tested is that the effects of ErbB-2 on multiple GJM regulators (p21cip1/WAF1 upregulation, Cdc2-Y15-p and survivin upregulation) can lead to GJM deregulation that contributes to anti-apoptosis. The long-term goals of this PPG are to improve strategies for the diagnosis and treatment of human breast cancer, especially in providing knowledge for better design rationale drugs to combat breast cancer.
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