A DOMINANT-NEGATIVE MUTANT OF THE INSULIN-LIKE GROWTH-FACTOR-I RECEPTOR INHIBITS THE ADHESION, INVASION, AND METASTASIS OF BREAST-CANCER

The 5-year survival rate for women with metastatic breast cancer is on ly 25-30%; thus, the need to improve treatment is apparent. Overexpres sion of insulin-like growth factor-I receptor (IGF-IR) correlates with poor prognosis and local recurrence. In this study, we addressed whet her functional impairment of IGF-IR affects adhesion, invasion, and me tastasis of breast cancer, Impairment of IGF-IR function was achieved by transfecting a dominant negative form of the receptor, termed 486st op, into MDA-MB-435 metastatic breast cancer cells, The protein produc t of 486stop is secreted extracellularly, resulting in a bystander eff ect. Cellular adhesion to laminin and collagen was inhibited 94 and 88 %, respectively. Furthermore, 486stop inhibited insulin-like growth fa ctor-I-stimulated invasion through collagen IV by 75%. The dominant ne gative receptor was secreted, as evidenced by the observation that MDA -MB-435 and MDA-MB-231 cells were prevented from binding to laminin by 90% when treated with conditioned medium (CM) from 486stop-transfecte d cells, CM also inhibited the invasion of MDA-MB-231 cells across col lagen IV by 80%, Finally, CM made MDA-MB-231 cells 30% more sensitive to Taxol(R)-induced cell death. Growth in soft agar was suppressed by 486stop, but growth in monolayer was unaffected. When injected into th e mammary fat pad, 486stop did not significantly suppress growth of th e primary tumor, but metastasis to the lungs, livers, lymph nodes, and lymph vessels was significantly decreased compared to the vector cont rol. In conclusion, inhibition of IGF-IR resulted in suppression of ad hesion, invasion, and metastasis, providing a mechanistic rationale fo r targeting IGF-IR in the treatment of metastatic breast cancer.