Prostate Development and Carcinogenesis in Prostate Specific ARKO Mice

The cre-lox ARKO mouse model provides a much-needed in vivo animal model system to study androgen functions in the selective androgen target tissues in male mice. In this regard, it is of paramount importance to derive a cre recombinant transgenic animal system with robust expression of a biologically active Cre protein in a prostate epithelial cell-specific manner. We selected a rat probasin (PB) promoter to drive expression of the Cre gene.13 The AR gene was gradually deleted during the adolescence stage when increased androgen levels activated the probasin promoter expression. Specific ARKO in prostate epithelium was evidenced by genotyping, RT-PCR and immunohistochemistry (IHC). Hormonal studies revealed normal serum testosterone levels in prostate-specific ARKO as compared to wild-type (WT) mice. The growth of urogenital organs other than prostate remained unchanged after the prostate epithelium no longer has a functional AR, however the size and weight of prostate glands were slightly decreased. The secretion proteins, probasin and prostatic secretory protein 94 (PSP94), were dramatically decreased in prostate-specific ARKO mice. When androgen ablation by castration was induced at 12 weeks old, both WT and prostate-specific ARKO mice showed dramatic regression of prostate and seminal vesicle growth. This model implies that the AR plays specific roles in epithelium and in stromal development. By crossing male probasin-cre mice to flox AR TRAMP female mice, the prostate-specific ARKO TRAMP mice were generated. This model will add more clues about the role of AR in the prostate cancer carcinogenesis and progression.

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