Inhibition of estradiol-induced mammary proliferation by dibenzoylmethane through the E2-ER-ERE-dependent pathway

• Published in: Carcinogenesis (New York) 2006, Vol.27 (1), p.131-136
• Main Authors: LIN, Chuan-Chuan, TSAI, Yun-Luen, HUANG, Mou-Tuan, LU, Yao-Ping, HO, Chi-Tang, TSENG, Shun-Fu, TENG, Shu-Chun
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Bromodeoxyuridine; Carcinogenesis, carcinogens and anticarcinogens; Cell Proliferation - drug effects; Chalcones - pharmacology; Chromatin Immunoprecipitation; Diet; Estradiol - pharmacology; Estrogen Antagonists - pharmacology; Female; Genes, ras - genetics; Humans; Injections, Intraperitoneal; Mammary Glands, Animal - cytology; Mammary Glands, Animal - drug effects; Mammary Glands, Animal - metabolism; Medical sciences; Mice; Mice, Inbred SENCAR; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Receptors, Estrogen - metabolism; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Telomerase - genetics; Telomerase - metabolism; Tumor Cells, Cultured; Tumors
• ISSN: 0143-3334; 1460-2180

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.