Inhibition of estradiol-induced mammary proliferation by dibenzoylmethane through the E 2 –ER–ERE-dependent pathway

Abstract

The phytochemical dibenzoylmethane (DBM) has been shown to inhibit 7,12-dimethylbenz[a]anthracene induced mammary tumorigenesis in Sencar mice. However, the molecular basis of this activity is still elusive. In the present study, we demonstrated that DBM inhibits estradiol (E2)-induced incorporation of bromodeoxyuridine into mammary DNA in immature female Sencar mice by 52%, when 10 micromol of DBM was intraperitoneally injected into mice prior to the injection of E2. Examination of the influence of DBM on the expressions of E2-ERE-dependent oncogenes in MCF-7 cells indicated that DBM inhibits the E2-induced cell growth as well as the expressions of four oncogenes, telomerase, c-myc, Ha-ras and bcl-2. Further mechanistic study using chromatin immunoprecipitation assay demonstrated that DBM acts as a pure antagonist by attenuating the binding of estrogen receptor to the estrogen response elements in the regulatory regions of c-myc, hTERT and bcl-2 genes in vivo. Taken together, our results strongly suggest that DBM plays an inhibitory role in E2-induced proliferations, which establishes DBM as a model molecule for studying the antiestrogenic drugs.