Role of IGFBP-3/IGFBP-3 Receptor Interaction in Normal and Malignant Mammary Growth: A Potential Diagnostic Parameter and New Strategy for Endocrine Therapy

Abstract

Abstract : This report will detail research accomplishments of the investigations of the biological actions of insulin-like growth factor binding protein 3 (IGFBP-3), which has been shown to exhibit activity in an IGF-independent manner. Data indicate that IGFBP-3 alone can bind to breast cancer cell surfaces, and subsequently exert inhibitory effects on cell growth. We have isolated, cloned, expressed, and purified a novel IGFBP-3 receptor, and demonstrated a specific interaction with IGFBP-3 in a human breast cancer cell system. To facilitate more detailed investigation into the interaction and functions of these two proteins, we have generated a polyclonal alpha 4-33 antibody which is specific and functional in a variety of immunoassays. We have also generated IGFBP-3 stably transfected human breast cancer cell lines, in which expression of IGFBP-3 is inducible. Additionally, we have localized the IGFBP-3 receptor binding domain within the mid-region of the IGFBP-3 molecule, residues 88-148. Finally, we have characterized the IGF-independent actions of IGFBP-3 in breast cancer cells, cell cycle arrest in G1/S phase and induction of apoptosis. The potential mechanisms responsible for those effects were elucidated that The IGFBP-3/IGFBP-3 receptor signaling pathway appears to cross-talk with MAPK signaling cascades, and thereby regulating cell cycle progression. Moreover, the IGFBP-3/IGFBP-3 receptor induces apoptosis through modulation of caspase activity. As completion of the proposed project, we believe that this project provides pivotal evidence for clinical significance and potential application of IGFBP-3 in the prevention and/or treatment of human neoplasia, particularly in conjunction with IGFBP-3 receptor.