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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.

Pubmed ID: 14678983


  • Freeman KW
  • Welm BE
  • Gangula RD
  • Rosen JM
  • Ittmann M
  • Greenberg NM
  • Spencer DM


Cancer research

Publication Data

December 1, 2003

Associated Grants

  • Agency: NCI NIH HHS, Id: R01-CA87569
  • Agency: NIAID NIH HHS, Id: T32-AI07495
  • Agency: NCI NIH HHS, Id: U01-CA84296

Mesh Terms

  • Animals
  • Cell Division
  • Disease Progression
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic
  • Prostatic Hyperplasia
  • Prostatic Intraepithelial Neoplasia
  • Prostatic Neoplasms
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptors, Fibroblast Growth Factor
  • Transgenes