3-Methylcholanthrene and other aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha.
3-Methylcholanthrene (3MC) is an aryl hydrocarbon receptor (AhR) agonist, and it has been reported that 3MC induces estrogenic activity through AhR-estrogen receptor alpha (ER alpha) 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 ER alpha but were not affected by the small inhibitory RNA for AhR. These results suggest that 3MC and PCB directly activate ER alpha, and this was confirmed in a competitive ER alpha binding assay and in a fluorescence resonance energy transfer experiment in which PCB and 3MC induced CFP-ER alpha/YFP-ER alpha interactions. In a chromatin immunoprecipitation assay, PCB and 3MC enhanced ER alpha (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 ER alpha-dependent transactivation and extend the number of ligands that activate both AhR and ER alpha.
Abdelrahim
Maen
M
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
Ariazi
Eric
E
Kim
Kyounghyun
K
Khan
Shaheen
S
Barhoumi
Rola
R
Burghardt
Robert
R
Liu
Shengxi
S
Hill
Denise
D
Finnell
Richard
R
Wlodarczyk
Bogdan
B
Jordan
V Craig
VC
Safe
Stephen
S
D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D019281:Dimerization; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008024:Ligands; D008748:Methylcholanthrene / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics; D014162:Transfection; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
D047628:Estrogen Receptor alpha; D008024:Ligands; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D019938:Cyclin D1; D004958:Estradiol; D008748:Methylcholanthrene; D011078:Polychlorinated Biphenyls; C023035:3,4,5,3',4'-pentachlorobiphenyl