Activation of beta-Catenin in mouse prostate causes HGPIN and continuous prostate growth after castration.
BACKGROUND
The role of Wnt/beta-Catenin signaling in embryogenesis and carcinogenesis has been extensively studied in organs such as colon, lung and pancreas, but little is known about Wnt/beta-Catenin signaling in the prostate. Although stabilizing mutations in APC and beta-Catenin are rare in primary prostate tumors, recent studies suggest that cytoplasmic/nuclear beta-Catenin is associated with advanced, metastatic, hormone-refractory prostate carcinoma.


METHODS
To better understand the role of beta-Catenin in prostatic development and carcinogenesis, we studied Wnt expression during prostate development and activated Wnt/beta-Catenin signaling in the developing and adult prostate.


RESULTS
Our results demonstrated that during prostate development Wnt ligands display a dynamic expression pattern. Activation of beta-Catenin during prostate development caused epithelial hyperplasia followed by prostatic intraepithelial neoplasia (PIN) in prostate. In the adult prostate, activation of beta-Catenin resulted in high grade PIN (HGPIN) and continuous prostatic growth after castration. As a result of activation of beta-Catenin, AR was first up-regulated with the emergence of epithelial hyperplasia, but was later down-regulated when HGPIN developed. Furthermore, activation of beta-Catenin induced Foxa2 re-expression in adult prostate which normally is only expressed in the embryonic budding stage during prostate development.


CONCLUSIONS
The results from this study strongly suggest that Wnt/beta-Catenin signaling is involved in the regulation of prostate development and confirm that constitutive activation of this pathway enables the mouse prostate to grow after castration.
Yu
Xiuping
X
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Wang
Yongqing
Y
Jiang
Ming
M
Bierie
Brian
B
Roy-Burman
Pradip
P
Shen
Michael M
MM
Taketo
Makoto Mark
MM
Wills
Marcia
M
Matusik
Robert J
RJ
D000367:Age Factors; D000728:Androgens / Q000378:metabolism; D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D009919:Orchiectomy; D011247:Pregnancy; D011467:Prostate / Q000254:growth & development / Q000502:physiology*; D019048:Prostatic Intraepithelial Neoplasia / Q000503:physiopathology*; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D000728:Androgens; C495267:CTNNB1 protein, mouse; C496503:Foxa2 protein, mouse; D018398:Homeodomain Proteins; C102837:Nkx3-1 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D051542:Hepatocyte Nuclear Factor 3-beta; C045073:Cre recombinase; D019426:Integrases