No. There is no evidence that persistent activation of the aryl hydrocarbon receptor (AhR) by itself results in cancer. There is, however, information that the AhR may be involved in the activation of specific P-450 enzymes that can result in an increased incidence of specific cancers in mammals. For example; the enzyme (P-450) responsible for the metabolism of Benzo[a]pyrene (BaP) to a form that binds DNA is enhanced by an AhR-dependent ligand interaction (dioxin-AhR). P-450 enhanced activity can be so great that the normal process by which the highly reactive BaP-diol-epoxide intermediate is detoxified becomes overwhelmed, resulting in increased DNA adduct formation. (See: http://en.wikipedia.org/wiki/Benzo(a)pyrene).

Note: Indole-3-carbinole has anti-tumor effects in mammals (See:

http://www.sciencedirect.com/science/article/pii/000927979290043K)

Sustained activation of AhR by its most potent ligand,TCDD (dioxin), has been linked to a broad range of toxic effects including tumor progression and carcinogenesis although, the mechanisms are still poorly understood. A couple of good reviews are, "Stephen Safe. Molecular biology of the Ah receptor and its role in carcinogenesis. Toxicology letters 120 (2001) 1-7" and "Prabir K. Mandal. Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. J Comp Physiol B (2005) 175: 221–230."

Although TCDD and other xenobiotics provide good examples, I was thinking more about effects of AhR ligands that are much more abundant and occur frequently in the diet.

A paper reported recently in Nature suggests indole metabolites produce an immunosuppressed environment that is permissive for tumor formation/progression.

And then there is this.....

Cancer Res. 2004 Jul 15;64(14):4707-10.

A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice.

Moennikes O, Loeppen S, Buchmann A, Andersson P, Ittrich C, Poellinger L, Schwarz M.

Source

Institut für Pharmakologie und Toxikologie, Abteilung Toxikologie, Universität Tübingen, Wilhelmstrasse 56, 72074 Tübingen, Germany.

Abstract

The dioxin/aryl hydrocarbon receptor (AhR) functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding enzymes involved in drug metabolism. Known ligands include polycyclic aromatic hydrocarbons, certain polychlorinated biphenyls, and the polyhalogenated dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin. Both polyhalogenated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin are potent promoters of rodent hepatocarcinogenesis in two-stage initiation-promotion experiments. Although several lines of evidence indicate the involvement of the AhR in toxic effects mediated by polyhalogenated biphenyls and dioxins, its involvement in tumor promotion has not been unequivocally proven. In the present study, a transgenic mouse line expressing a constitutively active AhR (CA-AhR) has been used to investigate the role of the AhR in hepatocarcinogenesis. Male AhR wild-type and CA-AhR-transgenic B6C3F1-mice were treated with a single injection of the hepatocarcinogen N-nitrosodiethylamine at 6 weeks of age and were subsequently kept untreated on control diet. Thirty five weeks after carcinogen treatment, mice were sacrificed, and the prevalence and multiplicity of liver tumors were determined. Whereas only 1 small liver tumor was observed in 15 AhR-wild-type mice, 19 tumors (two >1 cm in diameter) were present in 18 CA-AhR-transgenic mice. This result demonstrates the oncogenic potential of the activated AhR and implicates an important role of the receptor in promotion of hepatocarcinogenesis. A microarray-based gene expression-profiling analysis revealed down-regulation in the liver of CA-AhR-transgenic mice of a cluster of genes encoding heat shock proteins, including GRP78/BiP, Herp1, Hsp90, DnaJ (Hsp40) homologue B1, and Hsp105, which are important for protein folding and quality control.

PMID: 15256435

This is reference to the "endogenous ligand" paper in Nature.

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.

Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M.

Nature. 2011 Oct 5;478(7368):197-203. doi: 10.1038/nature10491.

PMID: 21976023

Too much AhR is no good, and too little is also no good. Still looking for the balance.

my limited understanding is that persistent AhR activation promotes high levels of xenobiotic-metabolizing enzymes (XMEs) that are themselves oxidative stress inducing. Phase II Antioxidant Response Elements (AREs) linked to the Nrf2 gene are needed to further metabolize the ligands, otherwise they just hang around and cause damage. Glutathione peroxidase and often the limiting factor of selenium are important in Phase II detox. enzymes.

ref. Köhle, Christoph and Bock, Karl Walter (2007). Coordinate regulation of Phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2. Biochemical pharmacology, 73(12): 1853-62.

The AhR-ligand complex binds to cis-acting dioxin-responsive enhancers (DREs) within the organism's DNA. For the well characterized dioxin-responsive P-450 CYP1A1, there are several DREs in the non-coding region in front of the gene, the binding of which (to AhR-dioxin) causes transcriptional activation. For some genes, the binding of the AhR-dioxin receptor-ligand complex to DRE(s) can cause up or even down regulatation of gene function (i.e., mRNA translation). Binding of the AHR-ligand to DNA occurs at the DRE, which is characterized as a wild type binding domain 5'-CGGAGTTGCGTGAGAAGAG-3' described by Lusska, et al., (1993) and Yao and Denison (1992).

[Lusska A., E. Shen and J.P. Whitlock Jr. 1993. Protein-DNA interactions at a dioxin-responsive enhancer. Analysis of six bona fide DNA-binding sites for the liganded Ah receptor. J. Biol. Chem. 268(9):6575-6580. Mar. 25.]

[Yao, E.F. and M.S. Denison. 1992. DNA sequence determinants for binding of transformed Ah receptor to a dioxin-responsive enhancer. Biochemistry. 31(21):5060-5067. Jun. 2.]

Within the DRE binding domain the middle 5 nucleotides (5'-GCGTG-3') are absolutely required for AhR-Ligand binding (regardless of ligand) and gene transcription activity. While certain of the surrounding nucleotides, around that core sequence, are required for binding, small differences (nucleotide substitution) can change the activity of the DRE from that which produces a great deal of gene transcription, to one that only enhances gene transcription a little bit, to even negative regulation of the gene transcription..