Several model systems have shown that the insulin-like growth factors (IGFs) are potent regulators of breast cancer growth. The applicant has demonstrated that neutralization of IGF action by IGF binding protein-1 (IGFBP-1), or interruption of type I IGF receptor (IGFR1) signaling by dominant-negative receptor constructs, inhibit breast cancer proliferation in vitro. The applicant has also identified the insulin-receptor substrate-1 (IRS-1) adaptor protein as a key molecule activated by IGFR1. Thus, IGF stimulation of breast cancer could be prevented at three levels: blockade of ligand/receptor interaction, interruption of IGFR1 autoactivation, and uncoupling of IGFR1 from downstream signaling pathways. Most of this work has thus far been based on human breast cancer cells in culture. The applicant now proposes to show that these anti-IGF strategies will effectively inhibit breast cancer growth in vivo in the more complex xenograft model system, as a prelude to designing new therapeutic strategies for clinical breast cancer.
His aims are: 1) to interfere with IGF ligand-receptor interactions by neutralizing IGF action by administering recombinant IGFBP-1 and by expressing IGFBP-1 in breast cancer cells; 2) to inhibit breast cancer growth by disrupting IGFR1 activation with the inducible expression and gene transfer of dominant negative receptor constructs, and 3) to inhibit function of the key IGFR1 substrate, IRS-1, by expressing an inducible anti-sense IRS-1 construct and by overexpressing an inhibitory adaptor protein (grb-IR), to uncouple the receptor from downstream signaling pathways. Identification of the key growth regulatory pathways in breast cancer cells has already proved to have enormous clinical value. For example, discovering the function of the estrogen receptor in the breast cancer cells has led to major advances in both prognosis and treatment. The IGF system appears to be at least equally important in stimulating breast cancer growth, and demonstrating targetable points in its functional pathway could well have an equally valuable impact on overall breast cancer treatment.
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