Molecular biology of the Ah receptor and its role in carcinogenesis

doi:10.1016/S0378-4274(01)00301-0

Toxicology Letters

Volume 120, Issues 1–3, 31 March 2001, Pages 1-7

https://doi.org/10.1016/S0378-4274(01)00301-0 Get rights and content

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear transcription factor that mediates responses to toxic halogenated aromatic toxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polynuclear aromatic hydrocarbons, combustion products, and numerous phytochemicals such as flavonoids and indole-3-carbinol (I3C). The nuclear AhR complex is a heterodimer containing the AhR and AhR nuclear translocator (Arnt) proteins, and the molecular mechanism of AhR action is associated with binding of the heterodimer to dioxin responsive elements (DREs) in regulatory regions of Ah-responsive genes. TCDD, a ‘xenodioxin’, is a multi-site carcinogen in several species and possibly in humans, whereas natural AhR ligands including I3C and flavonoids tend to protect against cancer. Both TCDD and phytochemicals inhibit estrogen-induced breast and endometrial cancer, and the molecular mechanisms of this common response will be described.

Introduction

The aryl hydrocarbon receptor (AhR) was first identified in mouse liver by Poland et al. (1976) who showed specific binding to radiolabeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic environmental toxicant that is a by-product of industrial processes and combustion of organic materials including municipal garbage. Subsequent studies with [³H]TCDD showed that the AhR was widely expressed in mammalian tissues, and it was hypothesized that initial binding to the AhR was linked to the broad spectrum of biochemical and toxic responses observed in laboratory animals and cells exposed to TCDD and other halogenated aromatic contaminants that bind the AhR (Poland and Knutson, 1982). For example, TCDD induces phase 1 and phase 2 drug metabolizing enzymes, modulates expression of many other genes/gene products and causes hepatoxic responses such as porphyria, immunotoxicity, developmental and reproductive toxicity, disruption of endocrine pathways, a wasting syndrome, chloracne, tumor promotion, and carcinogenesis. Interestingly, the toxic and genotoxic responses induced by TCDD are dependent on many factors including the age, sex, species and strain of experimental animal (Poland and Knutson, 1982). For example, dietary administration of TCDD for 2 years to Sprague–Dawley rats induces liver tumor formation in females, but not males, and this response appears to be linked to hormone expression (Kociba et al., 1978).

Section snippets

Mechanisms of AhR-mediated responses

The mechanism of AhR-mediated responses was initially investigated using CYP1A1 as a model (reviewed in Whitlock, 1993, Whitlock et al., 1996), and early studies showed that induction of CYP1A1 by TCDD was preceded by rapid formation of a 180–220 kD nuclear AhR complex. Subsequent studies showed that this complex was a heterodimer containing the AhR and AhR nuclear translocator (Arnt) protein, and both AhR and Arnt genes have been cloned and extensively characterized (Swanson and Bradfield, 1993

AhR-mediated carcinogenesis

The carcinogenic activity of TCDD and related compounds has recently been reviewed by a committee of scientists for the International Agency for Research on Cancer (IARC), and it was concluded by a majority of the committee that TCDD was a human carcinogen (Group 1) (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 1997). The major support for this designation was the animal studies (multi-site carcinogen) and the increased overall cancer mortality from industrial cohorts

Inhibitory AhR-ERα crosstalk: rodent uterus and human breast/endometrial cancer cell lines

The AhR is expressed in the rodent uterus and results of several studies showed that TCDD and other AhR agonists inhibited 17β-estradiol (E2)-induced uterine wet weight increase, cell proliferation, progesterone receptor (PR) binding, peroxidase activity, epidermal growth factor (EGF) receptor binding, and expression of c-fos and EGF receptor mRNA levels. TCDD has been extensively used to investigate AhR-mediated inhibition of E2-induced responses in various breast cancer cell lines. Initial

Mechanisms of inhibitory AhR-ERα crosstalk

The mechanisms of inhibitory AhR-ER crosstalk have also been investigated and several possible pathways could contribute to these interactions. For example, AhR agonists induce CYP1A1/A2 and this results in rapid metabolism and cellular depletion of 17β-estradiol (E2) in cell culture but not in vivo. Various AhR agonists induce ER degradation and this is related to proteasome-dependent degradation pathways. Prolonged depletion of cellular ER could contribute to loss of E2-responsiveness for

Development and applications of selective AhR modulators (SAhRMs)

The initial report that TCDD inhibits age-dependent formation of mammary tumors in female Sprague–Dawley rats (Kociba et al., 1978) has been confirmed in other rodent models. TCDD also inhibits carcinogen-induced mammary tumor growth and formation in rats and mammary tumor growth in athymic mice bearing breast cancer cell xenografts. Epidemiology studies in women accidentally exposed to TCDD in Seveso, Italy, show lower incidence rates of breast and endometrial cancer (Bertazzi et al., 1993).

Summary

The AhR is a ligand-activated nuclear transcription factor that binds toxic halogenated aromatic compounds, such as TCDD but also an increasing number of chemoprotective phytochemicals, which exhibit both AhR agonist and antagonist activities. Assessment of the noncarcinogenic and carcinogenic risks associated with exposure to trace levels of TCDD and related compounds in the diet invariably ignores interactions with high level exposure to phytochemical AhR agonists/antagonists. The research

Acknowledgements

The financial assistance of the National Institutes of Health (CA64081 and ES09106), DAMD 17-99-1-93-96 Avax Technologies and the Texas Agricultural Experiment Station is gratefully acknowledged.

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Molecular biology of the Ah receptor and its role in carcinogenesis

Abstract

Introduction

Section snippets

Mechanisms of AhR-mediated responses

AhR-mediated carcinogenesis

Inhibitory AhR-ERα crosstalk: rodent uterus and human breast/endometrial cancer cell lines

Mechanisms of inhibitory AhR-ERα crosstalk

Development and applications of selective AhR modulators (SAhRMs)

Summary

Acknowledgements

Toxicol. Appl. Pharmacol.

Cancer Lett.

Cancer Lett.

J. Biol. Chem.

Mol. Cell. Endocrinol.

Mol. Cell. Endocrinol.

FEBs

PCDDs, PCDFs, and PCBs in human milk from different parts of Norway and Lithuania

J. Toxicol. Environ. Health

Cancer incidence in a population accidentally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Epidemiology

Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

New Engl. J. Med.

Identification of a motif within the 5′-regulatory region on pS2 which is responsible for Ap1 binding and TCDD-mediated suppression

Biochemistry