Candidate's Abstract) The candidate's long-term objectives are to conduct breast cancer research at a medical school. Her primary interest is in the prevention and intervention of metastatic breast cancer. Conducting the research described below will help to identify environmental risk factors that can be modified to prevent the spread of breast cancer in women. Elevated levels of serum insulin-like growth factor-1 (IGF-1) is a risk factor for the development of advanced breast and prostate cancers. Why IGF-1 is elevated is not yet clear, but IGF-1 is known to be an endocrine factor that is regulated both by diet and estrogens. The candidate's laboratory has shown that reducing serum IGF-I through dietary restriction protects against the development of bladder cancer. Antiestrogenic drugs are also known to lower serum IGF-1 in women, therefore, these drugs are being investigated for their potential to prevent breast cancer. The candidate believes that lowering IGF- 1 may also prevent the spread of breast cancer. Their most recent work shows that IGF-1 signaling is necessary for breast cancer invasion and metastasis in an experimental model. To continue their work in this area they will focus on the signal transduction pathway downstream of IGF-1. They will test hypothesis the that IGF-1 stimulates the invasion of breast cancer cells through the phosphotidyl inositol 3-kinase (PI3K) pathway. Initially, the candidate will follow up on preliminary data showing that the inhibiton of P13K blocks IGF-1 stimulated invasion. Next, she will investigate how IGF-1 enhances the metastatic potential of breast cancer cells by determining if IGF-1 increases the expression of extracellular matrix degrading proteins. Finally, Dr. Dunn will inhibit the IGF-1/Pl3K pathway and determine what genes are differentially expressed using microarray. These studies will provide important information on the regulation of breast cancer metastasis by IGF-1 signaling, which may ultimately lead to risk-reduction strategies either through changes in the diet or by antiestrogens.
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