Activation of beta-Catenin in mouse prostate causes HGPIN and continuous prostate growth after castration.

Abstract

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.

• Authors: Xiuping Yu, Yongqing Wang, Ming Jiang, Brian Bierie, Pradip Roy-Burman, Michael M Shen, Makoto Mark Taketo, Marcia Wills, Robert J Matusik
• Journal: The Prostate (Prostate) Vol. 69 Issue 3 Pg. 249-62 (Feb 15 2009) ISSN: 1097-0045 [Electronic] United States
• PMID: 18991257 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Androgens
• CTNNB1 protein, mouse
• Foxa2 protein, mouse
• Homeodomain Proteins
• Nkx3-1 protein, mouse
• Transcription Factors
• Wnt Proteins
• beta Catenin
• Hepatocyte Nuclear Factor 3-beta
• Cre recombinase
• Integrases

Topics

• Age Factors
• Androgens (metabolism)
• Animals
• Female
• Gene Expression Regulation, Developmental
• Gene Expression Regulation, Neoplastic
• Hepatocyte Nuclear Factor 3-beta (genetics, metabolism)
• Homeodomain Proteins (genetics)
• Integrases (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mice, Nude
• Orchiectomy
• Pregnancy
• Prostate (growth & development, physiology)
• Prostatic Intraepithelial Neoplasia (physiopathology)
• Prostatic Neoplasms (physiopathology)
• Signal Transduction (physiology)
• Transcription Factors (genetics)
• Wnt Proteins (metabolism)
• beta Catenin (genetics, metabolism)