Conditional deletion of insulin-like growth factor-I receptor in prostate epithelium

Brent W. Sutherland, Sue E. Knoblaugh, Paula J. Kaplan-Lefko, Fen Wang, Martin Holzenberger, Norman M. Greenberg

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3495-3504
Number of pages10
JournalCancer research
Volume68
Issue number9
DOIs
StatePublished - May 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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