Abstract
The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the transgenic animals and are sensitive to inhibition by a novel small-molecule inhibitor of the IGF-IR kinase. This new model should provide new opportunities for further understanding how aberrant IGF-IR signaling leads to tumorigenesis and for optimizing novel antagonists of the receptor kinase.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / genetics*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Animals
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CD8 Antigens / biosynthesis
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CD8 Antigens / genetics
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Female
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Humans
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Mammary Neoplasms, Experimental / enzymology
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Mammary Neoplasms, Experimental / genetics*
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred ICR
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Mice, Nude
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Mice, Transgenic
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Neoplasm Transplantation
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Pregnancy
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / biosynthesis*
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Receptor, IGF Type 1 / genetics
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Salivary Gland Neoplasms / enzymology
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Salivary Gland Neoplasms / genetics*
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Salivary Gland Neoplasms / pathology
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Transfection
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Transgenes / genetics
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Transplantation, Heterologous
Substances
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CD8 Antigens
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Recombinant Fusion Proteins
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Receptor, IGF Type 1