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Dioxin and estrogen signaling in lung adenocarcinoma cells with different aryl hydrocarbon receptor/estrogen receptor ? phenotypes.

ABSTRACT: Evidence suggests that estrogen affects the pulmonary response to carcinogenic pollutants, such as dioxins. In this study, we examined dioxin and estrogen signaling cross-talk in lung adenocarcinoma cell lines that were engineered to exhibit different aryl hydrocarbon receptor (AhR)/estrogen receptor (ER) ? phenotypes. Data showed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) weakly antagonized estrogen-activated ER? activity in cells expressing abundant ER?, but little AhR. Increase of AhR expression or presence of a dioxin-responsive element in proximity silenced the antiestrogenic effect of TCDD. AhR was bound to dioxin-responsive element and transcriptionally active in both TCDD-untreated and -treated lung adenocarcinoma cells. 17?-estradiol (E2) reduced basal and TCDD-induced AhR activity only in ER?-positive cells. AhR and ER? exhibited a protein-protein interaction in the presence of E2. Cotreatment with TCDD moderated this protein interaction. Colocalization of ER? and AhR at the estrogen-responsive site under E2 and TCDD/E2 treatments implied that E2???ER? might hijack AhR away from the dioxin-responsive site. Increasing the relative expression of AhR to ER? counteracted inhibition of AhR activity by E2???ER?. When AhR and ER? were both highly expressed, TCDD and E2 up-regulated expression of dual-responsive genes cytochrome P450 (CYP) 1A1 and CYP1B1 in a cumulative manner, increasing the danger of metabolic activation of carcinogens. Whereas TCDD???AhR and E2???ER? appeared to regulate CYP1B1 separately through their binding sites, E2???ER? increased the TCDD responsiveness and mRNA expression of CYP1A1 in a noncanonical way. In conclusion, AhR/ER? expression pattern, estrogen level, and promoter context determine the genomic action of dioxin in lung adenocarcinoma cells.

SUBMITTER: Kuo LC

PROVIDER: S-EPMC5459550 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Dioxin and estrogen signaling in lung adenocarcinoma cells with different aryl hydrocarbon receptor/estrogen receptor α phenotypes.

Kuo Lun-Cheng LC Cheng Li-Chuan LC Lin Chun-Ju CJ Li Lih-Ann LA

American journal of respiratory cell and molecular biology 20131201 6

Evidence suggests that estrogen affects the pulmonary response to carcinogenic pollutants, such as dioxins. In this study, we examined dioxin and estrogen signaling cross-talk in lung adenocarcinoma cell lines that were engineered to exhibit different aryl hydrocarbon receptor (AhR)/estrogen receptor (ER) α phenotypes. Data showed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) weakly antagonized estrogen-activated ERα activity in cells expressing abundant ERα, but little AhR. Increase of AhR ex ...[more]

PMID: 23855798

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Project description:BackgroundCross-talk between the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER) plays a major role in signaling processes in female reproductive organs.ObjectivesWe investigated the influence of the AHR ligand 3-methylcholanthrene (3-MC) on ER-mediated signaling in mammary gland tissue of ovariectomized (ovx) rats.MethodsAfter 14 days of hormonal decline, ovx rats were treated for 3 days with 4 μg/kg 17β-estradiol (E2), 15 mg/kg 8-prenylnaringenin (8-PN), 15 mg/kg 3-MC, or a combination of these compounds (E2 + 3-MC, 8-PN + 3-MC). Whole-mount preparations of the mammary gland were used to count terminal end buds (TEBs). Protein expression studies (immunohistochemistry, immunofluorescence), a cDNA microarray, pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) were performed to evaluate the interaction between AHR- and ER-mediated signaling pathways.ResultsE2 treatment increased the number of TEBs and the levels of Ki-67 protein and progesterone receptor (PR); this treatment also changed the expression of 325 genes by more than 1.5-fold. Although 3-MC treatment alone had marginal impact on gene or protein expression, when rats were co-treated with 3-MC and E2, 3-MC strongly inhibited E2-induced TEB development, protein synthesis, and the expression of nearly half of E2-induced genes. This inhibitory effect of 3-MC was partially mirrored when 8-PN was used as an ER ligand. The anti-estrogenicity of ligand-activated AHR was at least partly due to decreased protein levels of ERα in ductal epithelial cells.ConclusionOur data show transcriptome-wide anti-estrogenic properties of ligand-activated AHR on ER-mediated processes in the mammary gland, thereby contributing an explanation for the chemopreventive and endocrine-disrupting potential of AHR ligands.CitationHelle J, Bader MI, Keiler AM, Zierau O, Vollmer G, Chittur SV, Tenniswood M, Kretzschmar G. 2016. Cross-talk in the female rat mammary gland: influence of aryl hydrocarbon receptor on estrogen receptor signaling. Environ Health Perspect 124:601-610; http://dx.doi.org/10.1289/ehp.1509680.

Dataset Information

Dioxin and estrogen signaling in lung adenocarcinoma cells with different aryl hydrocarbon receptor/estrogen receptor ? phenotypes.

Publications

Dioxin and estrogen signaling in lung adenocarcinoma cells with different aryl hydrocarbon receptor/estrogen receptor α phenotypes.

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