Carcinogenesis Advance Access originally published online on October 19, 2006
Carcinogenesis 2007 28(2):497-505; doi:10.1093/carcin/bgl179
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The aryl hydrocarbon receptor inhibits prostate carcinogenesis in TRAMP mice
1 School of Pharmacy, Molecular and Environmental Toxicology Center, University of Wisconsin Madison, WI, USA
2 Molecular and Environmental Toxicology Center, University of Wisconsin Madison, WI, USA
3 Center for Comparative Medicine, University of California Davis Davis, CA, USA
*To whom correspondence should be addressed at: The School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA. Tel: +1 608 263 5453; Fax: +1 608 265 3316; Email: repeterson{at}pharmacy.wisc.edu
The aryl hydrocarbon receptor (AhR) is a transcription factor that mediates the inhibitory effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on prostate growth and also modulates normal prostate development. This is evidenced by AhR null mice (Ahr–/–) having smaller dorsolateral and anterior prostates, even though all prostate lobes remain histologically normal. To test the hypothesis that loss of the AhR increases the rate of prostate carcinogenesis, the incidence of macroscopic prostate tumors was determined in Ahr+/+, Ahr+/– and Ahr–/– C57BL/6J transgenic adenocarcinoma of the mouse prostate (TRAMP) mice at 35, 70, 105, 140, 175 and 210 days of age. From 140 days, prostate tumor incidence was greater in Ahr–/– (60%) and Ahr+/– (43%) mice than in Ahr+/+ mice (16%). Allele quantification did not indicate a loss of the wild-type Ahr allele in heterozygous TRAMP tumors, suggesting that tumor formation in these mice was not due to a loss of Ahr heterozygosity. Prostatic SV40 large T antigen mRNA expression and protein localization were comparable in TRAMP mice of each Ahr genotype. Prostates from all mice of each Ahr genotype were histologically indistinguishable, exhibiting diffuse epithelial hyperplasia by 105 days of age. mRNA expression and protein localization for molecular markers of neuroendocrine differentiation, including chromogranin A and neuropilin-1, were elevated in prostate tumors compared to tumor-free ventral prostates, regardless of Ahr genotype or age. Taken together, these results demonstrate that the Ahr inhibits prostate carcinogenesis in C57BL/6J TRAMP mice by interfering with neuroendocrine differentiation.
Abbreviations: AhR, aryl hydrocarbon receptor; AR, androgen receptor; ARNT, AhR nuclear translocator; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Received July 12, 2006; revised September 11, 2006; accepted September 12, 2006.
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