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Abstract
Alterations of the Wnt/beta-catenin signaling pathway are positively associated with the development and progression of human cancer, including carcinoma of the prostate. To determine the role of activated Wnt/beta-catenin signaling in mouse prostate carcinogenesis, we created a mouse prostate tumor model using probasin-Cre-mediated deletion of Apc. Prostate tumors induced by the deletion of Apc have elevated levels of beta-catenin protein and are highly proliferative. Tumor formation is fully penetrant and follows a consistent pattern of progression. Hyperplasia is observed as early as 4.5 weeks of age, and adenocarcinoma is observed by 7 months. Continued tumor growth usually necessitated sacrifice between 12 and 15 months of age. Despite the high proliferation rate, we have not observed metastasis of these tumors to the lymph nodes or other organs. Surgical castration of 6-week-old mice inhibited tumor formation, and castration of mice with more advanced tumors resulted in the partial regression of specific prostate glands. However, significant areas of carcinoma remained 2 months postcastration, suggesting that tumors induced by Apc loss of function are capable of growth under conditions of androgen depletion. We conclude that the prostate-specific deletion of Apc and the increased expression of beta-catenin associated with prostate carcinoma suggests a role for beta-catenin in prostate cancer and offers an appropriate animal model to investigate the interaction of Wnt signaling with other genetic and epigenetic signals in prostate carcinogenesis.
Highlights
Prostate cancer is the second most common type of cancer and the third leading cause of cancer-related death in U.S men
We investigated the role of Wnt/h-catenin signaling in prostate cancer, using Cre-mediated recombination methods to create a conditional knockout of the Apc gene in prostate epithelial cells
We show that loss of Apc leads to the development of prostatic adenocarcinoma, positively correlated with increased cytoplasmic and nuclear levels of h-catenin
Summary
Prostate cancer is the second most common type of cancer and the third leading cause of cancer-related death in U.S men. Prostate-Specific Deletion of Apc the b-catenin gene have been shown to occur in prostate cancer [16,17,18] with >20% of advanced prostate tumors, 77% of prostatic lymph node metastases, and 85% of prostatic skeletal metastases having elevated levels of h-catenin [8, 19] It is unclear why dysregulation of h-catenin occurs so commonly in advanced skeletal disease but possible explanations include h-catenin–induced promiscuity of the androgen receptor Absence of tumor progression could reflect a level of hcatenin expression that was insufficient to induce malignant transformation but could signify that increased h-catenin expression alone was not sufficient to induce tumor formation To resolve this issue and to provide a robust and tractable mouse model of activated h-catenin signaling with which to study the role of h-catenin in prostate cancer, we created a conditional Apc mutant mouse. We show that inactivation of Apc leads to the rapid nuclear localization of h-catenin and a coordinated series of cellular changes leading to the emergence of androgen depletion– independent prostate cancer
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