Inhibition of estradiol-induced mammary proliferation by dibenzoylmethane through the E2-ER-ERE-dependent pathway.
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.
Lin
Chuan-Chuan
CC
Department of Food Science, China Institute of Technology, and National Taiwan University Hospital, Taipei, Taiwan.
Tsai
Yun-Luen
YL
Huang
Mou-Tuan
MT
Lu
Yao-Ping
YP
Ho
Chi-Tang
CT
Tseng
Shun-Fu
SF
Teng
Shu-Chun
SC
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects*; D047188:Chalcones / Q000494:pharmacology*; D047369:Chromatin Immunoprecipitation; D004032:Diet; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007274:Injections, Intraperitoneal; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018632:Mice, Inbred SENCAR; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D047188:Chalcones; D004965:Estrogen Antagonists; C489428:Myc protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol; C061481:dibenzoylmethane; D019098:Telomerase; C509187:Tert protein, mouse; D001973:Bromodeoxyuridine