Aryl hydrocarbon receptor ligands in cancer: friend and foe

Key Points

  • The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; commonly referred to as 'dioxin').

  • Three distinct classes of ligands bind to AHR: agonists, antagonists and selective AHR modulators. AHR is activated by endogenous ligands such as kynurenine, kynurenic acid and indoxyl sulphate, and physiologically relevant flora can produce potent AHR ligands from tryptophan.

  • Human AHR and mouse AHR exhibit substantial differences in ligand specificity, which might influence the progression of cancer. This complicates the validity of mouse models for studying the effects of AHR on human carcinogenesis.

  • Numerous studies demonstrate the ability of AHR to increase the proliferative and migratory potential of tumour cells.

  • AHR directly modulates inflammatory signalling, and AHR levels are often increased in tumours, probably as a result of inflammatory signalling. AHR agonist-mediated activity can have a key role in the production of regulatory T cells and thus could have a role in immune tolerance in cancer.

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as 'dioxin'. AHR influences the major stages of tumorigenesis — initiation, promotion, progression and metastasis — and physiologically relevant AHR ligands are often formed during disease states or during heightened innate and adaptive immune responses. Interestingly, ligand specificity and affinity vary between rodents and humans. Studies of aggressive tumours and tumour cell lines show increased levels of AHR and constitutive localization of this receptor in the nucleus. This suggests that the AHR is chronically activated in tumours, thus facilitating tumour progression. This Review discusses the role of AHR in tumorigenesis and the potential for therapeutic modulation of its activity in tumours.

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Figure 1: Agonist-mediated activation of AHR.
Figure 2: AHR activity within the tumour microenvironment.
Figure 3: Proposed mechanisms of cell cycle modulation by AHR.
Figure 4: Proposed role of AHR in tumour metastasis.

References

  1. 1

    Bersten, D. C., Sullivan, A. E., Peet, D. J. & Whitelaw, M. L. bHLH-PAS proteins in cancer. Nature Rev. Cancer 13, 827–841 (2013).

  2. 2

    Poland, A., Palen, D. & Glover, E. Tumour promotion by TCDD in skin of HRS/J hairless mice. Nature 300, 271–273 (1982).

  3. 3

    Sato, S. et al. Low-dose dioxins alter gene expression related to cholesterol biosynthesis, lipogenesis, and glucose metabolism through the aryl hydrocarbon receptor-mediated pathway in mouse liver. Toxicol. Appl. Pharmacol. 229, 10–19 (2008).

  4. 4

    Denison, M. S., Soshilov, A. A., He, G., DeGroot, D. E. & Zhao, B. Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol. Sci. 124, 1–22 (2011).

  5. 5

    Zhao, B. et al. Common commercial and consumer products contain activators of the aryl hydrocarbon (dioxin) receptor. PLoS ONE 8, e56860 (2013).

  6. 6

    Jeuken, A. et al. Activation of the Ah receptor by extracts of dietary herbal supplements, vegetables, and fruits. J. Agr. Food Chem. 51, 5478–5487 (2003).

  7. 7

    Hu, W., Sorrentino, C., Denison, M. S., Kolaja, K. & Fielden, M. R. Induction of Cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol. Pharmacol. 71, 1475–1486 (2007).

  8. 8

    Van der Heiden, E. et al. Food flavonoid aryl hydrocarbon receptor-mediated agonistic/antagonistic/synergic activities in human and rat reporter gene assays. Anal. Chim. Acta 637, 337–345 (2009).

  9. 9

    Zhang, S., Qin, C. & Safe, S. H. Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ. Health Perspect. 111, 1877–1882 (2003).

  10. 10

    Bjeldanes, L. F., Kim, J. Y., Grose, K. R., Bartholomew, J. C. & Bradfield, C. A. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc. Natl Acad. Sci. USA 88, 9543–9547 (1991). This study shows that the high-affinity AHR ligand indolo[3,2 b ]carbazole is produced in vivo from indole-3-carbinol.

  11. 11

    Jin, U. H. et al. Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities. Mol. Pharmacol. 85, 777–788 (2014).

  12. 12

    Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

  13. 13

    Fukumoto, S. et al. Identification of a probiotic bacteria-derived activator of the aryl hydrocarbon receptor that inhibits colitis. Immunol. Cell Biol. 92, 460–465 (2014).

  14. 14

    Magiatis, P. et al. Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin. J. Invest. Dermatol. 133, 2023–2030 (2013).

  15. 15

    van den Bogaard, E. H. et al. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J. Clin. Invest. 123, 917–927 (2013).

  16. 16

    Oesch-Bartlomowicz, B. et al. Aryl hydrocarbon receptor activation by cAMP versus dioxin: divergent signaling pathways. Proc. Natl Acad. Sci. USA 102, 9218–9223 (2005).

  17. 17

    Ikuta, T. et al. Nucleocytoplasmic shuttling of the aryl hydrocarbon receptor. J. Biochem. 127, 503–509 (2000).

  18. 18

    DiNatale, B. C. et al. Ah receptor antagonism represses head and neck tumor cell aggressive phenotype. Mol. Cancer Res. 10, 1369–1379 (2012). This study demonstrates that AHR antagonism inhibits constitutive AHR-mediated IL-6 production and migration, and the invasive phenotype in head and neck squamous cell carcinoma cells.

  19. 19

    Han, Z. et al. Aryl hydrocarbon receptor mediates laminar fluid shear stress-induced CYP1A1 activation and cell cycle arrest in vascular endothelial cells. Cardiovasc. Res. 77, 809–818 (2008).

  20. 20

    Conway, D. E. et al. Expression of CYP1A1 and CYP1B1 in human endothelial cells: regulation by fluid shear stress. Cardiovasc. Res. 81, 669–677 (2009).

  21. 21

    Murray, I. A. et al. Evidence that ligand binding is a key determinant of Ah receptor-mediated transcriptional activity. Arch. Biochem. Biophys. 442, 59–71 (2005).

  22. 22

    Bock, K. W. & Kohle, C. Ah receptor- and TCDD-mediated liver tumor promotion: clonal selection and expansion of cells evading growth arrest and apoptosis. Biochem. Pharmacol. 69, 1403–1408 (2005).

  23. 23

    Knerr, S. & Schrenk, D. Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in experimental models. Mol. Nutr. Food Res. 50, 897–907 (2006).

  24. 24

    Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007).

  25. 25

    Kennedy, G. D. et al. Liver tumor promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin is dependent on the aryl hydrocarbon receptor and TNF/IL-1 receptors. Toxicol. Sci. 140, 135–143 (2014). This study provides evidence that liver tumour promotion by activated AHR is dependent on inflammatory signalling.

  26. 26

    He, G. et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 155, 384–396 (2013).

  27. 27

    DiNatale, B. C., Schroeder, J. C., Francey, L. J., Kusnadi, A. & Perdew, G. H. Mechanistic insights into the events that lead to synergistic induction of interleukin 6 transcription upon activation of the aryl hydrocarbon receptor and inflammatory signaling. J. Biol. Chem. 285, 24388–24397 (2010). This study shows that AHR bound to DREs in the IL-6 promoter displaces HDAC1, leading to increased acetylation of RELA and synergistic induction of IL-6 transcription in the presence of an inflammatory signal.

  28. 28

    Schlezinger, J. J. et al. Direct assessment of cumulative aryl hydrocarbon receptor agonist activity in sera from experimentally exposed mice and environmentally exposed humans. Environ. Health Perspect. 118, 693–698 (2010).

  29. 29

    Connor, K. T. et al. AH receptor agonist activity in human blood measured with a cell-based bioassay: evidence for naturally occurring AH receptor ligands in vivo. J. Expo. Sci. Environ. Epidemiol. 18, 369–380 (2008).

  30. 30

    Adachi, J. et al. Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. J. Biol. Chem. 276, 31475–31478 (2001).

  31. 31

    Wincent, E. et al. The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans. J. Biol. Chem. 284, 2690–2696 (2009).

  32. 32

    Mezrich, J. D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010). This is the first study to link the activation of AHR by kynurenine with the generation of T Reg cells.

  33. 33

    Pilotte, L. et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl Acad. Sci. USA 109, 2497–2502 (2012).

  34. 34

    Stone, T. W., Stoy, N. & Darlington, L. G. An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol. Sci. 34, 136–143 (2013).

  35. 35

    Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011). This is a landmark study that correlates negative outcome in human brain cancer with levels of AHR and TDO2.

  36. 36

    DiNatale, B. C. et al. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin 6 in the presence of inflammatory signaling. Toxicol. Sci. 115, 89–97 (2010). This is the first report of an IDO1 product as a potent endogenous human AHR ligand.

  37. 37

    Botwinick, I. C. et al. A biological basis for depression in pancreatic cancer. HPB 16, 740–743 (2014).

  38. 38

    Schroeder, J. C. et al. The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry 49, 393–400 (2010).

  39. 39

    Niwa, T., Takeda, N., Tatematsu, A. & Maeda, K. Accumulation of indoxyl sulfate, an inhibitor of drug-binding, in uremic serum as demonstrated by internal-surface reversed-phase liquid chromatography. Clin. Chem. 34, 2264–2267 (1988).

  40. 40

    Meijers, B. K. et al. p-Cresyl sulfate and indoxyl sulfate in hemodialysis patients. Clin. J. Am. Soc. Nephrol. 4, 1932–1938 (2009).

  41. 41

    Sindhu, R. K. & Vaziri, N. D. Upregulation of cytochrome P450 1A2 in chronic renal failure: does oxidized tryptophan play a role? Adv. Exp. Med. Biol. 527, 401–407 (2003).

  42. 42

    Wong, G. et al. Time on dialysis and cancer risk after kidney transplantation. Transplantation 95, 114–121 (2013).

  43. 43

    Fan, Y. et al. The aryl hydrocarbon receptor functions as a tumor suppressor of liver carcinogenesis. Cancer Res. 70, 212–220 (2010).

  44. 44

    Ikuta, T. et al. ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice. Carcinogenesis 34, 1620–1627 (2013).

  45. 45

    Fritz, W. A., Lin, T. M., Cardiff, R. D. & Peterson, R. E. The aryl hydrocarbon receptor inhibits prostate carcinogenesis in TRAMP mice. Carcinogenesis 28, 497–505 (2007). This study establishes that expression of AHR represses prostate carcinogenesis in TRAMP mice.

  46. 46

    Moennikes, O. et al. A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res. 64, 4707–4710 (2004).

  47. 47

    Andersson, P. et al. A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc. Natl Acad. Sci. USA 99, 9990–9995 (2002). This report shows that the expression of a constitutively active mutant AHR in transgenic mice induces the formation of stomach tumours.

  48. 48

    Puga, A., Xia, Y. & Elferink, C. Role of the aryl hydrocarbon receptor in cell cycle regulation. Chem. Biol. Interact. 141, 117–130 (2002).

  49. 49

    John, K., Lahoti, T. S., Wagner, K., Hughes, J. M. & Perdew, G. H. The Ah receptor regulates growth factor expression in head and neck squamous cell carcinoma cell lines. Mol. Carcinog. 53, 765–776 (2013).

  50. 50

    Chuang, C. Y. et al. Up-regulation of osteopontin expression by aryl hydrocarbon receptor via both ligand-dependent and ligand-independent pathways in lung cancer. Gene 492, 262–269 (2012).

  51. 51

    Patel, R. D., Kim, D. J., Peters, J. M. & Perdew, G. H. The aryl hydrocarbon receptor directly regulates expression of the potent mitogen epiregulin. Toxicol. Sci. 89, 75–82 (2006).

  52. 52

    Roman, A. C., Carvajal-Gonzalez, J. M., Rico-Leo, E. M. & Fernandez-Salguero, P. M. Dioxin receptor deficiency impairs angiogenesis by a mechanism involving VEGF-A depletion in the endothelium and transforming growth factor-β overexpression in the stroma. J. Biol. Chem. 284, 25135–25148 (2009).

  53. 53

    Shigeishi, H. et al. Expression of epiregulin, a novel epidermal growth factor ligand associated with prognosis in human oral squamous cell carcinomas. Oncol. Rep. 19, 1557–1564 (2008).

  54. 54

    Wang, C. K. et al. Aryl hydrocarbon receptor activation and overexpression upregulated fibroblast growth factor-9 in human lung adenocarcinomas. Int. J. Cancer 125, 807–815 (2009).

  55. 55

    Nishimura, T. et al. Amphiregulin and epiregulin expression in neoplastic and inflammatory lesions in the colon. Oncol. Rep. 19, 105–110 (2008).

  56. 56

    Riese, D. J., 2nd & Cullum, R. L. Epiregulin: roles in normal physiology and cancer. Semin. Cell Dev. Biol. 28, 49–56 (2014).

  57. 57

    Zhu, Z. et al. Epiregulin is up-regulated in pancreatic cancer and stimulates pancreatic cancer cell growth. Biochem. Biophys. Res. Commun. 273, 1019–1024 (2000).

  58. 58

    Marlowe, J. L. & Puga, A. Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J. Cell Biochem. 96, 1174–1184 (2005).

  59. 59

    Elferink, C. J. Aryl hydrocarbon receptor-mediated cell cycle control. Prog. Cell Cycle Res. 5, 261–267 (2003).

  60. 60

    Vezina, C. M., Lin, T. M. & Peterson, R. E. AHR signaling in prostate growth, morphogenesis, and disease. Biochem. Pharmacol. 77, 566–576 (2009). This study shows that human prostrate tumours with an aggressive phenotype exhibit enhanced nuclear localization of AHR.

  61. 61

    Schlezinger, J. J. et al. A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. Biol. Chem. 387, 1175–1187 (2006).

  62. 62

    Feng, S., Cao, Z. & Wang, X. Role of aryl hydrocarbon receptor in cancer. Biochim. Biophys. Acta 1836, 197–210 (2013).

  63. 63

    Safe, S., Lee, S. O. & Jin, U. H. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol. Sci. 135, 1–16 (2013).

  64. 64

    Spink, D. C., Johnson, J. A., Connor, S. P., Aldous, K. M. & Gierthy, J. F. Stimulation of 17 β-estradiol metabolism in MCF-7 cells by bromochloro- and chloromethyl-substituted dibenzo-p-dioxins and dibenzofurans: correlations with antiestrogenic activity. J. Toxicol. Environ. Health 41, 451–466 (1994).

  65. 65

    Wormke, M. et al. The aryl hydrocarbon receptor mediates degradation of estrogen receptor α through activation of proteasomes. Mol. Cell. Biol. 23, 1843–1855 (2003).

  66. 66

    Ohtake, F., Fujii-Kuriyama, Y. & Kato, S. AhR acts as an E3 ubiquitin ligase to modulate steroid receptor functions. Biochem. Pharmacol. 77, 474–484 (2009).

  67. 67

    Safe, S. & Wormke, M. Inhibitory aryl hydrocarbon receptor–estrogen receptor α cross-talk and mechanisms of action. Chem. Res. Toxicol. 16, 807–816 (2003).

  68. 68

    Madak-Erdogan, Z. & Katzenellenbogen, B. S. Aryl hydrocarbon receptor modulation of estrogen receptor α-mediated gene regulation by a multimeric chromatin complex involving the two receptors and the coregulator RIP140. Toxicol. Sci. 125, 401–411 (2012).

  69. 69

    Beischlag, T. V. & Perdew, G. H. ERα-AHR-ARNT protein-protein interactions mediate estradiol-dependent transrepression of dioxin-inducible gene transcription. J. Biol. Chem. 280, 21607–21611 (2005).

  70. 70

    Dohr, O., Vogel, C. & Abel, J. Different response of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive genes in human breast cancer MCF-7 and MDA-MB 231 cells. Arch. Biochem. Biophys. 321, 405–412 (1995).

  71. 71

    Stark, K. et al. Reactivation of estrogen receptor α by vorinostat sensitizes mesenchymal-like triple-negative breast cancer to aminoflavone, a ligand of the aryl hydrocarbon receptor. PLoS ONE 8, e74525 (2013).

  72. 72

    Wihlen, B., Ahmed, S., Inzunza, J. & Matthews, J. Estrogen receptor subtype- and promoter-specific modulation of aryl hydrocarbon receptor-dependent transcription. Mol. Cancer Res. 7, 977–986 (2009).

  73. 73

    Terashima, J., Habano, W., Gamou, T. & Ozawa, S. Induction of CYP1 family members under low-glucose conditions requires AhR expression and occurs through the nuclear translocation of AhR. Drug Metab. Pharmacokinet. 26, 577–583 (2011).

  74. 74

    Vorrink, S. U. & Domann, F. E. Regulatory crosstalk and interference between the xenobiotic and hypoxia sensing pathways at the AhR-ARNT-HIF1α signaling node. Chem. Biol. Interact. 218, 82–88 (2014).

  75. 75

    Hamouchene, H., Arlt, V. M., Giddings, I. & Phillips, D. H. Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics 12, 333 (2011).

  76. 76

    Shin, S. et al. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol. Cell. Biol. 27, 7188–7197 (2007).

  77. 77

    Cho, Y. C., Zheng, W. & Jefcoate, C. R. Disruption of cell-cell contact maximally but transiently activates AhR-mediated transcription in 10T1/2 fibroblasts. Toxicol. Appl. Pharmacol. 199, 220–238 (2004).

  78. 78

    Ikuta, T., Kobayashi, Y. & Kawajiri, K. Cell density regulates intracellular localization of aryl hydrocarbon receptor. J. Biol. Chem. 279, 19209–19216 (2004).

  79. 79

    Diry, M. et al. Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism. Oncogene 25, 5570–5574 (2006).

  80. 80

    Peng, T. L., Chen, J., Mao, W., Song, X. & Chen, M. H. Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9. BMC Cell Biol. 10, 27 (2009).

  81. 81

    Niermann, T., Schmutz, S., Erne, P. & Resink, T. Aryl hydrocarbon receptor ligands repress T-cadherin expression in vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 300, 943–949 (2003).

  82. 82

    Dinatale, B. C. & Perdew, G. H. Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines. Mol. Carcinog. 50, 173–183 (2011).

  83. 83

    Bui, L. C. et al. Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity. Oncogene 28, 3642–3651 (2009).

  84. 84

    Fernandez-Salguero, P. M. A remarkable new target gene for the dioxin receptor: The Vav3 proto-oncogene links AhR to adhesion and migration. Cell Adh Migr 4, 172–175 (2010).

  85. 85

    Ikuta, T. & Kawajiri, K. Zinc finger transcription factor Slug is a novel target gene of aryl hydrocarbon receptor. Exp. Cell Res. 312, 3585–3594 (2006). This study shows that AHR exhibits increased nuclear localization at low cellular densities and participates in the induction and regulation of tumour cell invasion.

  86. 86

    Belguise, K. et al. Green tea polyphenols reverse cooperation between c-Rel and CK2 that induces the aryl hydrocarbon receptor, slug, and an invasive phenotype. Cancer Res. 67, 11742–11750 (2007).

  87. 87

    Hsu, E. L. et al. A proposed mechanism for the protective effect of dioxin against breast cancer. Toxicol. Sci. 98, 436–444 (2007).

  88. 88

    Jin, U. H., Lee, S. O., Pfent, C. & Safe, S. The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis. BMC Cancer 14, 498 (2014).

  89. 89

    Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).

  90. 90

    Fardel, O. Cytokines as molecular targets for aryl hydrocarbon receptor ligands: implications for toxicity and xenobiotic detoxification. Expert Opin. Drug Metab. Toxicol. 9, 141–152 (2013).

  91. 91

    Haarmann-Stemmann, T., Bothe, H. & Abel, J. Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways. Biochem. Pharmacol. 77, 508–520 (2009).

  92. 92

    Sekine, H. et al. Hypersensitivity of aryl hydrocarbon receptor-deficient mice to lipopolysaccharide-induced septic shock. Mol. Cell. Biol. 29, 6391–6400 (2009).

  93. 93

    Lahoti, T. S. et al. Aryl hydrocarbon receptor antagonism attenuates growth factor expression, proliferation, and migration in fibroblast-like synoviocytes from patients with rheumatoid arthritis. J. Pharmacol. Exp. Ther. 348, 236–245 (2014).

  94. 94

    Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nature Immunol. 11, 854–861 (2010). This study shows that AHR promotes T Reg cell production through binding to MAF and inducing the expression of IL-10 and IL-21.

  95. 95

    Hollingshead, B. D., Beischlag, T. V., Dinatale, B. C., Ramadoss, P. & Perdew, G. H. Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells. Cancer Res. 68, 3609–3617 (2008).

  96. 96

    Furman, D. P., Oshchepkova, E. A., Oshchepkov, D. Y., Shamanina, M. Y. & Mordvinov, V. A. Promoters of the genes encoding the transcription factors regulating the cytokine gene expression in macrophages contain putative binding sites for aryl hydrocarbon receptor. Comput. Biol. Chem. 33, 465–468 (2009).

  97. 97

    Vogel, C. F. et al. Aryl hydrocarbon receptor signaling regulates NF-κB RelB activation during dendritic-cell differentiation. Immunol. Cell Biol. 91, 568–575 (2013).

  98. 98

    Vogel, C. F. et al. Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression. Am. J. Pathol. 171, 1538–1548 (2007).

  99. 99

    Degner, S. C., Papoutsis, A. J., Selmin, O. & Romagnolo, D. F. Targeting of aryl hydrocarbon receptor-mediated activation of cyclooxygenase-2 expression by the indole-3-carbinol metabolite 3,3′-diindolylmethane in breast cancer cells. J. Nutr. 139, 26–32 (2009).

  100. 100

    Tian, Y., Ke, S., Denison, M. S., Rabson, A. B. & Gallo, M. A. Ah receptor and NF-κB interactions, a potential mechanism for dioxin toxicity. J. Biol. Chem. 274, 510–515 (1999). This is the first report demonstrating that AHR can interact with NF-κB.

  101. 101

    Vogel, C. F. et al. RelB, a new partner of aryl hydrocarbon receptor-mediated transcription. Mol. Endocrinol. 21, 2941–2955 (2007).

  102. 102

    Kim, D. W. et al. The RelA NF-κB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene 19, 5498–5506 (2000).

  103. 103

    Vogel, C. F., Sciullo, E. & Matsumura, F. Involvement of RelB in aryl hydrocarbon receptor-mediated induction of chemokines. Biochem. Biophys. Res. Commun. 363, 722–726 (2007).

  104. 104

    Vogel, C. F. et al. Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression. Arch. Biochem. Biophys. 512, 78–86 (2011).

  105. 105

    Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nature Rev. Immunol. 6, 295–307 (2006).

  106. 106

    Corthay, A. Does the immune system naturally protect against cancer? Front. Immunol. 5, 197 (2014).

  107. 107

    Darrasse-Jeze, G. & Podsypanina, K. How numbers, nature, and immune status of Foxp3 regulatory T-cells shape the early immunological events in tumor development. Front. Immunol. 4, 292 (2013).

  108. 108

    Marshall, N. B., Vorachek, W. R., Steppan, L. B., Mourich, D. V. & Kerkvliet, N. I. Functional characterization and gene expression analysis of CD4+ CD25+ regulatory T cells generated in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. J. Immunol. 181, 2382–2391 (2008).

  109. 109

    Gandhi, R. et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells. Nature Immunol. 11, 846–853 (2010).

  110. 110

    Funatake, C. J., Marshall, N. B. & Kerkvliet, N. I. 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters the differentiation of alloreactive CD8+ T cells toward a regulatory T cell phenotype by a mechanism that is dependent on aryl hydrocarbon receptor in CD4+ T cells. J. Immunotoxicol 5, 81–91 (2008).

  111. 111

    Kerkvliet, N. I., Shepherd, D. M. & Baecher-Steppan, L. T lymphocytes are direct, aryl hydrocarbon receptor (AhR)-dependent targets of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD): AhR expression in both CD4+ and CD8+ T cells is necessary for full suppression of a cytotoxic T lymphocyte response by TCDD. Toxicol. Appl. Pharmacol. 185, 146–152 (2002). This study provides the first in vivo evidence that TCDD can directly suppress a cytotoxic T lymphocyte response.

  112. 112

    Kerkvliet, N. I. et al. Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. Immunotherapy 1, 539–547 (2009).

  113. 113

    Benson, J. M. & Shepherd, D. M. Aryl hydrocarbon receptor activation by TCDD reduces inflammation associated with Crohn's disease. Toxicol. Sci. 120, 68–78 (2011).

  114. 114

    Singh, N. P. et al. Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLoS ONE 6, e23522 (2011).

  115. 115

    Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).

  116. 116

    Punj, S. et al. Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease. PLoS ONE 9, e88726 (2014).

  117. 117

    Wang, H. K. et al. Dietary flavonoid naringenin induces regulatory T cells via an aryl hydrocarbon receptor mediated pathway. J. Agr. Food Chem. 60, 2171–2178 (2012).

  118. 118

    Luster, M. I. et al. 1-amino-3,7,8-trichlorodibenzo-p-dioxin: a specific antagonist for TCDD-induced myelotoxicity. Biochem. Biophys. Res. Commun. 139, 747–756 (1986).

  119. 119

    Merchant, M., Arellano, L. & Safe, S. The mechanism of action of α-naphthoflavone as an inhibitor of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced CYP1A1 gene expression. Arch. Biochem. Biophys. 281, 84–89 (1990).

  120. 120

    Gasiewicz, T. A. & Rucci, G. α-naphthoflavone acts as an antagonist of 2,3,7,8-tetrachlorodibenzo-p-dioxin by forming an inactive complex with the Ah receptor. Mol. Pharmacol. 40, 607–612 (1991).

  121. 121

    Henry, E. C. et al. Flavone antagonists bind competitively with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the aryl hydrocarbon receptor but inhibit nuclear uptake and transformation. Mol. Pharmacol. 55, 716–725 (1999).

  122. 122

    Murray, I. A. et al. Antagonism of aryl hydrocarbon receptor signaling by 6,2′,4′-trimethoxyflavone. J. Pharmacol. Exp. Ther. 332, 135–144 (2010).

  123. 123

    Ciolino, H. P., Daschner, P. J. & Yeh, G. C. Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor. Cancer Res. 58, 5707–5712 (1998).

  124. 124

    Kim, S. H. et al. Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol. Pharmacol. 69, 1871–1878 (2006).

  125. 125

    Boitano, A. E. et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329, 1345–1348 (2010). This study reports the development of a high-affinity AHR antagonist that promotes the proliferation of human haematopoietic stem cells in vitro and that demonstrates therapeutic potential.

  126. 126

    Smith, K. J. et al. Identification of a high affinity ligand that exhibits complete Ah receptor antagonism. J. Pharmacol. Exp. Ther. 338, 318–327 (2011).

  127. 127

    Brembilla, N. C. et al. In vivo dioxin favors interleukin-22 production by human CD4+ T cells in an aryl hydrocarbon receptor (AhR)-dependent manner. PLoS ONE 6, e18741 (2011).

  128. 128

    Zhao, B., Degroot, D. E., Hayashi, A., He, G. & Denison, M. S. CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor. Toxicol. Sci. 117, 393–403 (2010).

  129. 129

    Lewis, J. S. & Jordan, V. C. Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat. Res. 591, 247–263 (2005).

  130. 130

    Safe, S. & McDougal, A. Mechanism of action and development of selective aryl hydrocarbon receptor modulators for treatment of hormone-dependent cancers (Review). Int. J. Oncol. 20, 1123–1128 (2002).

  131. 131

    Steffan, R. J. et al. Synthesis and activity of substituted 4-(indazol-3-yl)phenols as pathway-selective estrogen receptor ligands useful in the treatment of rheumatoid arthritis. J. Med. Chem. 47, 6435–6438 (2004).

  132. 132

    Chadwick, C. C. et al. Identification of pathway-selective estrogen receptor ligands that inhibit NF-κB transcriptional activity. Proc. Natl Acad. Sci. USA 102, 2543–2548 (2005).

  133. 133

    Murray, I. A. et al. Evidence for ligand-mediated selective modulation of aryl hydrocarbon receptor activity. Mol. Pharmacol. 77, 247–254 (2010).

  134. 134

    Murray, I. A. et al. Development of a selective modulator of aryl hydrocarbon (Ah) receptor activity that exhibits anti-inflammatory properties. Chem. Res. Toxicol. 23, 955–966 (2010).

  135. 135

    Murray, I. A. et al. Suppression of cytokine-mediated complement factor gene expression through selective activation of the Ah receptor with 3′,4′-dimethoxy-α-naphthoflavone. Mol. Pharmacol. 79, 508–519 (2011).

  136. 136

    Astroff, B. et al. 6-Methyl-1,3,8-trichlorodibenzofuran as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist: inhibition of the induction of rat cytochrome P-450 isozymes and related monooxygenase activities. Mol. Pharmacol. 33, 231–236 (1988).

  137. 137

    Zacharewski, T. et al. 6-Methyl-1,3,8-trichlorodibenzofuran (MCDF) as an antiestrogen in human and rodent cancer cell lines: evidence for the role of the Ah receptor. Toxicol. Appl. Pharmacol. 113, 311–318 (1992).

  138. 138

    McDougal, A., Wilson, C. & Safe, S. Inhibition of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumor growth by aryl hydrocarbon receptor agonists. Cancer Lett. 120, 53–63 (1997).

  139. 139

    Zhang, S. et al. The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Endocr. Relat. Cancer 16, 835–844 (2009).

  140. 140

    Zhang, S. et al. Aryl hydrocarbon receptor agonists induce microRNA-335 expression and inhibit lung metastasis of estrogen receptor negative breast cancer cells. Mol. Cancer Ther. 11, 108–118 (2012).

  141. 141

    Manchester, D. K., Gordon, S. K., Golas, C. L., Roberts, E. A. & Okey, A. B. Ah receptor in human placenta: stabilization by molybdate and characterization of binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 3-methylcholanthrene, and benzo(a)pyrene. Cancer Res. 47, 4861–4868 (1987).

  142. 142

    Flaveny, C. A., Murray, I. A. & Perdew, G. H. Differential gene regulation by the human and mouse aryl hydrocarbon receptor. Toxicol. Sci. 114, 217–225 (2010).

  143. 143

    Forgacs, A. L., Dere, E., Angrish, M. M. & Zacharewski, T. R. Comparative analysis of temporal and dose-dependent TCDD-elicited gene expression in human, mouse, and rat primary hepatocytes. Toxicol. Sci. 133, 54–66 (2013).

  144. 144

    Black, M. B. et al. Cross-species comparisons of transcriptomic alterations in human and rat primary hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Sci. 127, 199–215 (2012).

  145. 145

    Flaveny, C., Reen, R. K., Kusnadi, A. & Perdew, G. H. The mouse and human Ah receptor differ in recognition of LXXLL motifs. Arch. Biochem. Biophys. 471, 215–223 (2008).

  146. 146

    Ramadoss, P. & Perdew, G. H. Use of 2-azido-3-[125I]iodo-7,8-dibromodibenzo-p-dioxin as a probe to determine the relative ligand affinity of human versus mouse aryl hydrocarbon receptor in cultured cells. Mol. Pharmacol. 66, 129–136 (2004).

  147. 147

    Flaveny, C. A., Murray, I. A., Chiaro, C. R. & Perdew, G. H. Ligand selectivity and gene regulation by the human aryl hydrocarbon receptor in transgenic mice. Mol. Pharmacol. 75, 1412–1420 (2009).

  148. 148

    Saito, R. et al. Aryl hydrocarbon receptor in breast cancer — a newly defined prognostic marker. Horm. Cancer 5, 11–21 (2014).

  149. 149

    Richmond, O. et al. The aryl hydrocarbon receptor is constitutively active in advanced prostate cancer cells. PLoS ONE 9, e95058 (2014).

  150. 150

    Yin, X. F., Chen, J., Mao, W., Wang, Y. H. & Chen, M. H. Downregulation of aryl hydrocarbon receptor expression decreases gastric cancer cell growth and invasion. Oncol. Rep. 30, 364–370 (2013).

  151. 151

    Su, J. M., Lin, P. & Chang, H. Prognostic value of nuclear translocation of aryl hydrocarbon receptor for non-small cell lung cancer. Anticancer Res. 33, 3953–3961 (2013).

  152. 152

    Liu, Z. et al. AhR expression is increased in hepatocellular carcinoma. J. Mol. Histol. 44, 455–461 (2013).

  153. 153

    Tanaka, G. et al. Induction and activation of the aryl hydrocarbon receptor by IL-4 in B cells. Int. Immunol. 17, 797–805 (2005).

  154. 154

    Vogel, C. F. et al. Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-κB. J. Biol. Chem. 289, 1866–1875 (2014).

  155. 155

    Beischlag, T. V., Luis Morales, J., Hollingshead, B. D. & Perdew, G. H. The aryl hydrocarbon receptor complex and the control of gene expression. Crit. Rev. Eukaryot. Gene Expr. 18, 207–250 (2008).

  156. 156

    Mellor, A. L. et al. Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J. Immunol. 171, 1652–1655 (2003).

  157. 157

    Litzenburger, U. M. et al. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR. Oncotarget 5, 1038–1051 (2014).

  158. 158

    Kolluri, S. K., Weiss, C., Koff, A. & Gottlicher, M. p27Kip1 induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells. Genes Dev. 13, 1742–1753 (1999).

  159. 159

    Pang, P. H. et al. Molecular mechanisms of p21 and p27 induction by 3-methylcholanthrene, an aryl-hydrocarbon receptor agonist, involved in antiproliferation of human umbilical vascular endothelial cells. J. Cell. Physiol. 215, 161–171 (2008).

  160. 160

    Puga, A. et al. Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest. J. Biol. Chem. 275, 2943–2950 (2000).

  161. 161

    Barhoover, M. A., Hall, J. M., Greenlee, W. F. & Thomas, R. S. Aryl hydrocarbon receptor regulates cell cycle progression in human breast cancer cells via a functional interaction with cyclin-dependent kinase 4. Mol. Pharmacol. 77, 195–201 (2010).

  162. 162

    Denison, M. S. & Nagy, S. R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43, 309–334 (2003).

  163. 163

    Poland, A., Glover, E. & Kende, A. S. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J. Biol. Chem. 251, 4936–4946 (1976).

  164. 164

    Farrell, K., Safe, L. & Safe, S. Synthesis and aryl hydrocarbon receptor binding properties of radiolabeled polychlorinated dibenzofuran congeners. Arch. Biochem. Biophys. 259, 185–195 (1987).

  165. 165

    Jensen, B. A., Reddy, C. M., Nelson, R. K. & Hahn, M. E. Developing tools for risk assessment in protected species: relative potencies inferred from competitive binding of halogenated aromatic hydrocarbons to aryl hydrocarbon receptors from beluga (Delphinapterus leucas) and mouse. Aquat. Toxicol. 100, 238–245 (2010).

  166. 166

    Kolasa, E., Houlbert, N., Balaguer, P. & Fardel, O. AhR- and NF-κB-dependent induction of interleukin-6 by co-exposure to the environmental contaminant benzanthracene and the cytokine tumor necrosis factor-α in human mammary MCF-7 cells. Chem. Biol. Interact. 203, 391–400 (2013).

  167. 167

    Gillner, M., Bergman, J., Cambillau, C., Fernstrom, B. & Gustafsson, J. A. Interactions of indoles with specific binding sites for 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver. Mol. Pharmacol. 28, 357–363 (1985).

  168. 168

    Jin, U. H., Lee, S. O. & Safe, S. Aryl hydrocarbon receptor (AHR)-active pharmaceuticals are selective AHR modulators in MDA-MB-468 and BT474 breast cancer cells. J. Pharmacol. Exp. Ther. 343, 333–341 (2012).

  169. 169

    O'Donnell, E. F. et al. The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. PLoS ONE 5, e13128 (2010).

  170. 170

    Quattrochi, L. C. & Tukey, R. H. Nuclear uptake of the Ah (dioxin) receptor in response to omeprazole: transcriptional activation of the human CYP1A1 gene. Mol. Pharmacol. 43, 504–508 (1993).

  171. 171

    Ciolino, H. P., Daschner, P. J. & Yeh, G. C. Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochem. J. 340, 715–722 (1999).

  172. 172

    Oberg, M., Bergander, L., Hakansson, H., Rannug, U. & Rannug, A. Identification of the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole, in cell culture medium, as a factor that controls the background aryl hydrocarbon receptor activity. Toxicol. Sci. 85, 935–943 (2005).

  173. 173

    Savouret, J. F. et al. 7-ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor. J. Biol. Chem. 276, 3054–3059 (2001).

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Acknowledgements

The authors would like to thank M. H. Perdew for critically reviewing the manuscript. The authors apologize to those whose work is not cited owing to space limitations. The authors' research is funded by US National Institutes of Health grants (ES004869, ES019964 and ES022186).

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Correspondence to Gary H. Perdew.

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Glossary

2,3,7,8-tetrachlorodibenzo-p-dioxin

(TCDD). A polycyclic halogenated hydrocarbon that is highly toxic to rodents and that exhibits high affinity for the aryl hydrocarbon receptor.

Polycyclic aromatic hydrocarbons

A group of more than 100 different stable organic molecules comprised of only carbon and hydrogen. They are large, planar molecules assembled from a collection of fused benzene-like rings. They are formed during the incomplete burning of coal, oil, gas, garbage or other organic substances such as tobacco or charbroiled meat.

Barrier function

The integrity of a protective epithelial layer that serves as a barrier and allows selective absorption.

Antagonists

In the context of this Review, aryl hydrocarbon receptor (AHR) ligands that inhibit canonical dioxin-responsive element (DRE)-mediated and non-DRE-mediated AHR activity.

TRAMP

(Transgenic adenocarcinoma of mouse prostate). A mouse prostate cancer model in which mice that express SV40 T/t antigens that are under the control of the androgen-sensitive rat probasin promoter develop focal adenocarcinomas with 100% frequency between 10 and 20 weeks of age.

Epithelial–mesenchymal transition

The process by which cells convert from an epithelial to a mesenchymal phenotype. This process, which occurs during normal embryonic development, can be abnormally activated in carcinomas, resulting in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

Weak agonist

In the context of this Review, this refers to an aryl hydrocarbon receptor ligand that displays partial agonist activity, eliciting a sub-maximal dioxin-responsive element-mediated transcriptional response. In addition, in the presence of a strong agonist, a weak agonist will exhibit antagonist activity.

Selective AHR modulators

(SAHRMs). Aryl hydrocarbon receptor (AHR) ligands that display functional selectivity, exhibiting negligible dioxin-responsive element (DRE)-mediated transcriptional responses while maximally stimulating non-DRE mediated AHR activity.

Full agonist

In the context of this Review, an aryl hydrocarbon receptor ligand that maximally elicits canonical dioxin-responsive element-mediated transcriptional responses.

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Murray, I., Patterson, A. & Perdew, G. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 14, 801–814 (2014). https://doi.org/10.1038/nrc3846

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