Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition.
Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance.
Acevedo
Victor D
VD
Program in Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Gangula
Rama D
RD
Freeman
Kevin W
KW
Li
Rile
R
Zhang
Youngyou
Y
Wang
Fen
F
Ayala
Gustavo E
GE
Peterson
Leif E
LE
Ittmann
Michael
M
Spencer
David M
DM
D000818:Animals; D019281:Dimerization; D018450:Disease Progression; D004789:Enzyme Activation; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006609:High Mobility Group Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008648:Mesoderm / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis*; D012074:Remission Induction; D055758:SOX9 Transcription Factor; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D006609:High Mobility Group Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D014157:Transcription Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1