title: Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor.
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.
authors.affiliation: Oncology Drug Discovery and Discovery Toxicology, Bristol-Myers Squibb Research Institute, Princeton, New Jersey 08534, USA.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.forename: Darryl L
authors.initials: DL
authors.lastname: Hadsell
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Rowley
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: David K
authors.initials: DK
authors.lastname: Bol
authors.forename: Amy E
authors.initials: AE
authors.lastname: Camuso
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardis
authors.forename: Ann F
authors.initials: AF
authors.lastname: Greer
authors.forename: Ching Ping
authors.initials: CP
authors.lastname: Ho
authors.forename: Warren
authors.initials: W
authors.lastname: Hurlburt
authors.forename: Aixin
authors.initials: A
authors.lastname: Li
authors.forename: Mark
authors.initials: M
authors.lastname: Saulnier
authors.forename: Upender
authors.initials: U
authors.lastname: Velaparthi
authors.forename: Cindy
authors.initials: C
authors.lastname: Wang
authors.forename: Mei-Li
authors.initials: ML
authors.lastname: Wen
authors.forename: Richard A
authors.initials: RA
authors.lastname: Westhouse
authors.forename: Mark
authors.initials: M
authors.lastname: Wittman
authors.forename: Kurt
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Brent A
authors.initials: BA
authors.lastname: Rupnow
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
mesh_terms: 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
chemical_list: D016827:CD8 Antigens; D011993:Recombinant Fusion Proteins; D017526:Receptor, IGF Type 1