The aryl hydrocarbon receptor inhibits prostate carcinogenesis in TRAMP mice.
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.
Fritz
Wayne A
WA
School of Pharmacy, Molecular and Environmental Toxicology Center, University of Wisconsin Madison, WI 53705, USA.
Lin
Tien-Min
TM
Cardiff
Robert D
RD
Peterson
Richard E
RE
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D001483:Base Sequence; D001835:Body Weight; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D053379:Chromogranin A / Q000235:genetics; D017931:DNA Primers; D018628:Gene Dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D039942:Neuropilin-1 / Q000235:genetics; D011471:Prostatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000502:physiology*
D000952:Antigens, Polyomavirus Transforming; D053379:Chromogranin A; D017931:DNA Primers; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; D039942:Neuropilin-1