ARYL-HYDROCARBON RECEPTOR-MEDIATED ANTIESTROGENIC AND ANTITUMORIGENICACTIVITY OF DIINDOLYLMETHANE

Phytochemicals such as indole-3-carbinol (I3C) and sulforaphane are co mponents of cruciferous vegetables which exhibit antitumorigenic activ ity associated with altered carcinogen metabolism and detoxification, Diindolyl-methane (DIM) is a major acid-catalyzed metabolite of I3C fo rmed in the gut that binds to the aryl hydrocarbon receptor (AhR) and treatment of MCF-7 human breast cancer cells with 10-50 mu M DIM resul ted in rapid formation of the nuclear AhR complex and induction of CYP 1A1 gene expression was observed at concentrations >50 mu M, Previous studies have demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TC DD), a high affinity AhR ligand, inhibits 17 beta-estradiol (E2)-induc ed responses in MCF-7 cells and growth of E2-dependent 7,12-dimethylbe nzanthracene (DMBA)-induced mammary tumors in female Sprague-Dawley ra ts. Results of this study show that like TCDD, DIM inhibits E2-induced proliferation of MCF-7 cells, reporter gene activity in cells transie ntly transfected with an E2-responsive plasmid (containing a frog vite llogenin A2 gene promoter insert) and down-regulates the nuclear estro gen receptor, Moreover, DIM (5 mg/kg every other day) also inhibits DM BA-induced mammary tumor growth in Sprague-Dawley rats and this was no t accompanied by induction of hepatic CYP1A1-dependent activity, Thus, DLM represents a new class of relatively non-toxic AhR-based antiestr ogens that inhibit Ea-dependent tumor growth in rodents and current st udies are focused on development of analogs for clinical treatment of breast cancer.