| With increasing evidence suggesting a role for the IGF-axis in breast cancer and a number of IGF-IR-targeted therapeutics currently in clinical trials, the purpose of this study was to further the knowledge of IGF-IR-mediated mammary tumorigenesis through examining primary tumor growth, metastasis and resistance to IGF-IR downregulation in our inducible transgenic model. In MTB-IGFIR mice, metastases, ranging from small microscopic lesions to larger macroscopic tumors, were observed to occur in 41.5% of animals. This process was associated with upregulation of ILK and cyclin D1. Independence during IGF-IR downregulation was studied in transgenic animals and the primary RM11A cell line and was linked to retention of cyclin D1 upregulation, loss of membranous beta-catenin and upregulation of PDGF receptor isoforms. The role of PDGFRalpha and beta was further evaluated during this process; downregulation of these receptors was associated with increased survival and proliferation with a concurrent decrease in apoptosis. Knockdown of PDGF receptors was also shown to inhibit cell migration and invasion. The role of the well known breast cancer oncogene ErbB2 during IGF-IR-mediated mammary tumorigenesis was also investigated. During this process, ErbB2 was co-ordinately overexpressed with IGF-IR activation. In RM11A cells overexpressing the IGF-IR, ErbB2 enhanced tumorigenesis by decreasing tumor latency and enhancing proliferation after cell seeding. ErbB2 also contributed to resistance to IGF-IR downregulation and was associated with metastasis. In conclusion, this study was important for identifying other proteins that can augment IGF-IR-mediated tumorigenesis and promote resistance to oncogene withdrawal. |
