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REVIEWS
Aryl hydrocarbon receptor ligands in cancer: friend and foe
Iain A.Murray, Andrew D.Patterson and Gary H.Perdew
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.
2,3,7,8tetrachlorodibenzo
pdioxin
(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 benzenelike rings. They are formed during the incomplete burning of coal, oil, gas, garbage or other organic substances such as tobacco or charbroiled meat.
The aryl hydrocarbon receptor (AHR) is a member of the basic helixloophelixPERARNTSIM (bHLHPAS) subgroup of the bHLH superfamily of transcription factors and is the only member of this family known to be activated by ligands1. AHR was discovered as the receptor that binds 2,3,7,8tetrachlorodibenzopdioxin (TCDD; also known as dioxin) with high affinity; this receptor is capable of sustained hyperactivation, resulting in a myriad of toxicological outcomes. The half-life of TCDD in humans is approximately 10years owing to its inability to be metabolized to a polar derivative that can be excreted. These properties contribute to the potency of TCDD as a promoter of liver and skin carcinogenesis in rodents2. After heterodimerization with the AHR nuclear translocator (ARNT), AHR can induce the transcription of several cytochrome P450 (CYP) enzymes that are important in the metabolism and bioactivation of carcinogens, particularly polycyclic aromatic hydrocarbons (FIG.1). DNA microarray studies have established that AHR either directly or...