The Role of Insulin-Like Growth Factor (IGF) in IGF-Mediated Tumorigenesis

The insulin-like growth factor (IGF) system has been shown to play an important role in the progression of a number of cancers, including breast cancer. IGF-1 binds with high affinity to a family of proteins known as the IGF binding proteins (IGFBPs), which act as natural inhibitors of IGF-1 through sequestration from the IGF-1 receptor. The purpose of this proposal is the development of IGF antagonists based on the structure of the IGFBPs. Knowledge of the mechanism of IGFBP action is currently unclear, therefore we have taken a photoaffinity labeling approach to identify the IGF binding domains on the IGFBPs. Previous data collected in the lab indicate that the carboxy terminus of IGFBP-2 is involved in high affinity binding to IGF-1; these experiments are being repeated with IGFBP-3 and IGFBP-5 to extend these findings. Current photoaffinity labeling data indicate that the midregion of the IGFBP-3 protein is involved in IGF-1 binding. This information will be used in the rational design of therapeutic IGF antagonists for use in the treatment of breast and other cancers.