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.