Cooperation between Stat3 and Akt Signaling Leads to Prostate Tumor Development in Transgenic Mice

In this report, we describe the development of a transgenic mouse in which a rat probasin promoter (ARR(2)Pb) was used to direct prostate specific expression of a constitutively active form of signal transducer and activator of transcription 3 (i.e., Stat3C). ARR(2)Pb.Stat3C mice exhibited hyperplasia and prostate intraepithelial neoplasia (PIN) lesions in both ventral and dorsolateral prostate lobes at 6 and 12 months; however, no adenocarcinomas were detected. The effect of combined loss of PTEN was examined by crossing ARR(2)Pb.Stat3C mice with PTEN+/- null mice. PTEN+/- null mice on an ICR genetic background developed only hyperplasia and PIN at 6 and 12 months, respectively. ARR(2)Pb.Stat3C x PTEN+/- mice exhibited a more severe prostate phenotype compared with ARR(2)Pb.Stat3C and PTEN+/- mice. ARR(2)Pb.Stat3C x PTEN+/- mice developed adenocarcinomas in the ventral prostate as early as 6 months (22% incidence) that reached an incidence of 61% by 12 months. Further evaluations indicated that phospho-Stat3, phospho-Akt, phospho-nuclear factor kappa B, cyclin D1, and Ki67 were upregulated in adenocarcinomas from ARR(2)Pb.Stat3C x PTEN+/- mice. In addition, membrane staining for beta-catenin and E-cadherin was reduced. The changes in Stat3 and nuclear factor kappa B phosphorylation correlated most closely with tumor progression. Collectively, these data provide evidence that Stat3 and Akt signaling cooperate in prostate cancer development and progression and that ARR(2)Pb.Stat3C x PTEN+/- mice represent a novel mouse model of prostate cancer to study these interactions.