3-Methylcholanthrene and other aryl hydrocarbon receptor agonists directly activate estrogen receptor α

Maen Abdelrahim, Eric Ariazi, Kyounghyun Kim, Shaheen Khan, Rola Barhoumi, Robert Burghardt, Shengxi Liu, Denise Hill, Richard Finnell, Bogdan Wlodarczyk, V. Craig Jordan, Stephen Safe

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98 Scopus citations

Abstract

3-Methylcholanthrene (3MC) is an aryl hydrocarbon receptor (AhR) agonist, and it has been reported that 3MC induces estrogenic activity through AhR-estrogen receptor α (ERα) interactions. In this study, we used 3MC and 3,3′,4,4′,5-pentachlorobiphenyl (PCB) as prototypical AhR ligands, and both compounds activated estrogen-responsive reporter genes/gene products (cathepsin D) in MCF-7 breast cancer cells. The estrogenic responses induced by these AhR ligands were inhibited by the antiestrogen ICI 182780 and by the transfection of a small inhibitory RNA for ERα but were not affected by the small inhibitory RNA for AhR. These results suggest that 3MC and PCB directly activate ERα, and this was confirmed in a competitive ERα binding assay and in a fluorescence resonance energy transfer experiment in which PCB and 3MC induced CFP-ERα/YFP-ERα interactions. In a chromatin immunoprecipitation assay, PCB and 3MC enhanced ERα (but not AhR) association with the estrogen-responsive region of the pS2 gene promoter. Moreover, in AhR knockout mice, 3MC increased uterine weights and induced expression of cyclin D1 mRNA levels. These results show that PCB and 3MC directly activate ERα-dependent transactivation and extend the number of ligands that activate both AhR and ERα.

Original languageEnglish (US)
Pages (from-to)2459-2467
Number of pages9
JournalCancer research
Volume66
Issue number4
DOIs
StatePublished - Feb 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Abdelrahim, M., Ariazi, E., Kim, K., Khan, S., Barhoumi, R., Burghardt, R., Liu, S., Hill, D., Finnell, R., Wlodarczyk, B., Jordan, V. C., & Safe, S. (2006). 3-Methylcholanthrene and other aryl hydrocarbon receptor agonists directly activate estrogen receptor α. Cancer research, 66(4), 2459-2467. https://doi.org/10.1158/0008-5472.CAN-05-3132