Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor.
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.
Carboni
Joan M
JM
Oncology Drug Discovery and Discovery Toxicology, Bristol-Myers Squibb Research Institute, Princeton, New Jersey 08534, USA.
Lee
Adrian V
AV
Hadsell
Darryl L
DL
Rowley
Bruce R
BR
Lee
Francis Y
FY
Bol
David K
DK
Camuso
Amy E
AE
Gottardis
Marco
M
Greer
Ann F
AF
Ho
Ching Ping
CP
Hurlburt
Warren
W
Li
Aixin
A
Saulnier
Mark
M
Velaparthi
Upender
U
Wang
Cindy
C
Wen
Mei-Li
ML
Westhouse
Richard A
RA
Wittman
Mark
M
Zimmermann
Kurt
K
Rupnow
Brent A
BA
Wong
Tai W
TW
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016827:CD8 Antigens / Q000096:biosynthesis / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011247:Pregnancy; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012468:Salivary Gland Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D019076:Transgenes / Q000235:genetics; D014183:Transplantation, Heterologous
D016827:CD8 Antigens; D011993:Recombinant Fusion Proteins; D017526:Receptor, IGF Type 1