|Carboni, Joan - BRISTOL-MYERS RES. INST.|
|Lee, Adrian - BAYLOR COLL MEDICINE|
|Hadsell, Darryl - BAYLOR COLL MEDICINE|
|Rowley, Bruce - BRISTOL-MYERS RES. INST.|
|Lee, Francis - BRISTOL-MYERS RES. INST.|
|Bol, David - BRISTOL-MYERS RES. INST.|
|Camuso, Amy - BRISTOL-MYERS RES. INST.|
|Gottardis, Marco - BRISTOL-MYERS RES. INST.|
|Ho, Ching Ping - BRISTOL-MYERS RES. INST.|
|Hurlburt, Warren - BRISTOL-MYERS RES. INST.|
Submitted to: Cancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 1, 2005
Publication Date: May 1, 2005
Citation: Carboni, J.M., Lee, A.V., Hadsell, D.L., Rowley, B.R., Lee, F.Y., Bol, D.K., Camuso, A.E., Gottardis, M., Ho, C., Hurlburt, W. 2005. Tumor development by transgenic expression of a constitutively active Insulin-Like Growth Factor I receptor. Cancer Research. 65:3781-3781. Interpretive Summary: Insulin-like growth factor and its receptor, the type 1 IGF receptor, are two proteins that play important roles in both normal development and cancer. In the mammary gland loss of these proteins impairs normal development while overexpression of them can cause cancer. This paper describes the consequences of overexpressing a constitutively activated form of the type 1 IGF receptor in transgenic mice. Mice that carry this IGF-I receptor transgene have both abnormal mammary development and increased frequency of cancer in both the mammary gland and salivary gland. The transgenic mice described in this paper are also used as tools to test the effectiveness of drugs with potential anti-cancer activity. Thus these mice may also be useful in screening anti-tumor drugs for use in humans.
Technical 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.