The mechanism of hormone reflactory prostate cancer in PTEN gene conditional targeting mouse

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Introduction and Objective: The tumor suppressor gene MMAC/PTEN, located on chromosome10q23.3 is frequently inactivated in a variety of tumors such as prostate cancer and functions as a negative regulator of Akt activation in PI3-kinase-Akt signal pathway. Based on Cre/loxP system, we developed the PTEN conditional gene targeting in mouse prostate. By crossbreeding PSA-Cre transgenic mice with PTEN-loxP/loxP mice, and subsequent breeding of monoallelic PTEN deletion mice (PSA-Cre, PTEN-loxP/+) together bears offspring with biallelic PTEN deletion mice (PSA-Cre, PTEN-loxP/loxP). In these mice, prostate specific deletion of PTEN leads to prostate carcinogenesis and its progression. In this study, we have demonstrated that a prostate specific biallelic deletion of PTEN in mouse prostate causes prostate cancer. Furthermore, we have investigated the mechanism of hormone refractory prostate cancer induced after castration in PTEN conditional gene targeting mice.

Materials and Methods: The mice with prostate specific deletion of PTEN from PSA-Cre, PTEN-loxP/loxP were genetically confirmed by PCR, and each prostate was examined for histopathological and immunohistochemical examination at each time point. To test the efficacy of testosterone on the mice with prostate specific deletion of PTEN, the mice were castrated 6 weeks after birth, and the prostate was observed thereafter.

Results:

PIN lesions were observed in all of mice with prostate specific biallelic deletion of PTEN after 6 weeks and development of prostate cancer at 3 months. Lung metastases were also observed in 50% of mice at 10 months. The mice with prostate specific monoallelic deletion of PTEN took more time to develop PIN lesions in 50% mice from 10 to 14 months, resulting in prostate carcinoma development in 40% of mice thereafter. In prostate cancer tissues, phospho-Akt expression was significantly up-regulated compared to the normal prostate gland. Furthermore, castration resulted in an efficacy of prostate atrophy in mice with both monoallelic and bialelic deletion of PTEN. Surprisingly, however, prostate cancer cells derived from biallelic deletion of PTEN kept surviving and progressing like hormone refractory prostate cancer even after castration.

Conclusions: This mouse model demonstrated that PTEN plays an important role in prostate carcinogenesis and hormone independent mechanism.