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Conditional Deletion of Insulin-like Growth Factor-I Receptor in Prostate Epithelium

¹ Clinical Research Division and ² Animal Health Shared Resources, Fred Hutchinson Cancer Research Center; ³ Department of Pharmacology, University of Washington, Seattle, Washington; ⁴ Department of Molecular and Cellular Biology, Baylor College of Medicine; ⁵ Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and ⁶ Institut National de la Sante et de la Recherche Medicale U515, Saint-Antoine Hospital, Paris, France

Requests for reprints: Norman M. Greenberg, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109. Phone: 206-667-4433; Fax: 206-667-4930; E-mail: ngreenberg{at}fhcrc.org.

Key Words: IGF-I • IGF-IR • Cre-Lox • prostate • mouse model

Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that can influence growth, differentiation, and survival of cells expressing the cognate type 1 receptor (IGF-IR). To better understand cell autonomous IGF-IR signaling in the epithelial compartment of the prostate gland, we generated a conditional (Cre/loxP) prostate-specific IGF-IR knockout mouse model. In contrast to epidemiologic studies that established a correlation between elevated serum IGF-I and the risk of developing prostate cancer, we show that abrogation of IGF-IR expression in the dorsal and lateral prostate could activate extracellular signal-regulated kinase 1/2 signaling and cause cell autonomous proliferation and hyperplasia. Moreover, persistent loss of IGF-IR expression in dorsal and ventral lobes induced p53-regulated apoptosis and cellular senescence rescue programs, predicting that titration of IGF-IR signaling might facilitate growth of tumors with compromised p53 activity. Therefore, we crossed the mice carrying the prostate-specific IGF-IR knockout alleles into the transgenic adenocarcinoma of the mouse prostate model that is driven, in part, by T antigen–mediated functional inactivation of p53. Consistent with our prediction, prostate epithelial–specific deletion of IGF-IR accelerated the emergence of aggressive prostate cancer when p53 activity was compromised. Collectively, these data support a critical role for IGF-IR signaling in prostate tumorigenesis and identify an important IGF-IR–dependent growth control mechanism. [Cancer Res 2008;68(9):3495–504]