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The aryl hydrocarbon receptor (AhR) is a signal transduction protein that binds 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and mediates its effects on gene expression in various organs including prostate. We previously demonstrated that the AhR is necessary for normal prostate development and inhibits tumor formation in C57Bl/6J transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. We also observed chronic prostatitis in 500-day old C57Bl/6J mice, though the severity of lymphocyte infiltration in these prostates was not dependent on dioxin exposure. It has been postulated that chronic inflammation may play a role in prostate carcinogenesis. To investigate whether Ahr-null expression can alter the pathologic progression of inducible prostatitis, we infected 10-week old Ahr-wildtype and -null C57Bl/6J mice with uropathogenic E. coli 1677 via an intraurethral route. Prostate histopathology was evaluated 5 days and 5, 10 and 20 weeks after infection. The following histologic features were observed in both wildtype and null mice. A mild sub-acute inflammatory reaction was evident in prostates 5 days post infection. The inflammation became chronic at 5 weeks, by 10 weeks was almost gone, and by 20 weeks no inflammation was found. Mild focal epithelial hyperplasia was observed in the dorsolateral prostates and coagulating glands at 5 weeks and throughout the study. Focal epithelial hyperplasia in the infected ventral prostate (VP) also started at 5 weeks and the hyperplasia broadened and became diffuse at 20 weeks. Atypical epithelia were observed occasionally in the VP at 5 weeks. Even though no inflammation remained, the degree of dysplasia intensified until 20 weeks when focal dysplastic pockets were observed. Proliferating cell nuclear antigen (PCNA) immunoreactivity was clustered with the hyperplastic/dysplastic lesions in the VP at 20 weeks. Glutathione S-transferase π 1 (GSTP1) expression was elevated in the VP 20 weeks post infection while expression of NK-3 transcription factor locus 1 (NKX3.1), phosphatase and tensin homolog (Pten) and cyclin-dependent kinase inhibitor 1B (p27Kip1) were decreased. These changes in gene expression mirror those seen in human prostate cancer and support a proposed prostatitis-cancer model. Even though Ahr expression did not seem to alter this prostatitis-dysplasia progression, we demonstrated that the dysplastic changes induced by prostatitis are not dependent on a persistent inflammatory reaction. Supported by NIH grants CA095751, ES01332 and DK061574.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA