Inducible ARKO and Arko Tramp Mice

The normal prostate development depends on the androgen-AR signaling. In the total ARKO model, agenesis of prostate revealed that AR plays a critical role in the embryonic development of prostate. The prostate-specific ARKO model using probasin-cre lox strategy had nearly normal prostate growth after adolescence. These two models suggested the time-specific role of AR in the development of prostate. What is the role of AR between embryonic and adolescence? The time-specific role of AR in the normal prostate development can also be elucidated by the study of the inducible ARKO mice. The method uses an interferon-responsive promoter to control the expression of Cre recombinase. Here, Cre was used to delete a segment of the AR gene flanked by loxP recombinase recognition sites. Deletion was complete in liver and nearly complete in lymphocytes within a few days, whereas partial deletion was obtained in other tissues. Crossing the flox-AR female mice with Mx-1-inducible Cre male mice17 will generate interferon-inducible ARKO mice. Our preliminary data (Xu and Chang, unpublished data), showed the efficiency of deletion of AR gene in prostate tissue was about 20% using the intraperitoneal injection of pI-pC. Some modifications can be made to improve the percentage of AR deletion, such as multiple injections and intra-prostate injection. Yet the partial deletion of AR in prostate may be sufficient for gene inactivation and result in easily detectable phenotypes. By crossing TRAMP male mice with flox-AR-cre-MX-1 female mice, the inducible ARKO TRAMP mice can be generated. As in Fig. 2, induction of IFN in 5-week-old inducible ARKO TRAMP mice resulted in a prostate tumor in one out of three mice, while all three mice without the induction of IFN had prominent prostate tumors at 20-week-old. If the AR gene was inducibly knocked out in 20-week-old mice, all the mice in WT AR and inducible ARKO groups grew prostate cancer, but the tumor size was smaller in the ARKO group. This model indicated that AR deletion in TRAMP mice might inhibit carcinogenesis at an earlier stage and delay cancer progression at a late stage. Further study is necessary to confirm the results of the preliminary observations and to explore the actual role of AR in prostate cancer carcinogenesis and progression.

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