Inducible prostate intraepithelial neoplasia with reversible hyperplasia in conditional FGFR1-expressing mice.
Accurate determination of the contributions of oncogenes toward tumor progression requires their regulation. Herein, we created transgenic mice with prostate-specific expression of ligand-inducible FGFR1 or FGFR2, based on lipid-permeable dimerizing molecules, called chemical inducers of dimerization. Despite extensive homology and equivalent expression by both chimeric receptors in the ventral prostate gland, only FGFR1 triggers detectable nuclear translocation of Erk and progression to prostatic intraepithelial neoplasia (PIN). Induction of PIN grade I-II, indicated by multiple layers of atypical cells, is seen consistently by 12 weeks of chemical inducers of dimerization treatment. By 6 months, more extensive nuclear atypia, thickened "reactive" stroma, and basement membrane herniation occurs, corresponding to PIN IV. By timed removal of FGFR1 signaling, we show that induced hyperplasia is reversible until extensive intraductal vascularization occurs, but continued progression requires prolonged FGFR1 signaling. Additionally, by highlighting differences between the two receptors and creating the foundation for controlling FGFR1 signaling during prostate cancer progression, a model of early stage prostate cancer is established for developing targeted intervention directed toward the FGFR signaling axis.
Freeman
Kevin W
KW
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Welm
Bryan E
BE
Gangula
Rama D
RD
Rosen
Jeffrey M
JM
Ittmann
Michael
M
Greenberg
Norman M
NM
Spencer
David M
DM
D000818:Animals; D002455:Cell Division / Q000502:physiology; D018450:Disease Progression; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019048:Prostatic Intraepithelial Neoplasia / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D019076:Transgenes
D017468:Receptors, Fibroblast Growth Factor; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2