Interaction of the aryl hydrocarbon receptor ligand 6-methyl-1,3,8-trichlorodibenzofuran with estrogen receptor alpha.
The polycyclic aromatic hydrocarbon 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) is related to the industrial byproduct dioxin and is a weak agonist and partial antagonist at the aryl hydrocarbon receptor (AhR). Tamoxifen is used for the treatment and prevention of breast cancer and interferes with the interaction of estrogen with estrogen receptor alpha (ER). The combination of MCDF and tamoxifen lowered the effective dose of both drugs required to inhibit 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in rats and protected against the estrogenic effects of tamoxifen on the uterus in rats (A. McDougal et al., Cancer Res 2001;61:3902-7), pointing to the potential use of MCDF in breast cancer treatment. Potential AhR-ER cross-talk is evidenced by the antiestrogenic activity of MCDF and the degradative effect of MCDF on ER protein levels. Our studies confirmed that MCDF degraded the ER. MCDF displayed antiestrogenic activity at higher concentrations in MCF-7 human breast cancer cells, but MCDF alone (10(-6) M) stimulated the growth of MCF-7 cells. MCDF also activated an estrogen response element (ERE)-luciferase reporter and increased mRNA levels of the estrogen-responsive gene transforming growth factor (TGF)-alpha. The estrogenic effects of MCDF are ER dependent because they were blocked by the pure antiestrogen ICI 182,780. MCDF induced ER-coactivator interaction in glutathione S-transferase pull-down assays and the formation of an ER.ERE complex in gel mobility shift assays, further indicating that the estrogenic actions of MCDF are mediated by the ER. In addition, knockdown of the AhR with small interfering RNA did not affect MCDF-induced ERE-luciferase activity. Overall, these data support the conclusion that MCDF is a partial agonist at the ER. This study provides the first evidence for the direct interaction of the ER with MCDF and challenges the view that MCDF is simply an AhR-specific ligand.
Pearce
Sandra Timm
ST
Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
Liu
Hong
H
Radhakrishnan
Ishwar
I
Abdelrahim
Maen
M
Safe
Stephen
S
Jordan
V Craig
VC
D051792:Basic Helix-Loop-Helix Proteins; D001572:Benzofurans / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D006801:Humans; D008958:Models, Molecular; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk / Q000502:physiology; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D001572:Benzofurans; D004958:Estradiol; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D016211:Transforming Growth Factor alpha; C111235:AHR protein, human; C054923:6-methyl-1,3,8-trichlorodibenzofuran