Conditional deletion of insulin-like growth factor-I receptor in prostate epithelium.
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.
Sutherland
Brent W
BW
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Knoblaugh
Sue E
SE
Kaplan-Lefko
Paula J
PJ
Wang
Fen
F
Holzenberger
Martin
M
Greenberg
Norman M
NM
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D004848:Epithelium / Q000378:metabolism*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D011467:Prostate / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism
D017526:Receptor, IGF Type 1; C045073:Cre recombinase; D019426:Integrases