title: Oestrogenic activity of tamoxifen and its metabolites on gene regulation and cell proliferation in MCF-7 breast cancer cells.
abstract: The effects of tamoxifen, three of its in vivo metabolites and 3-hydroxytamoxifen on cellular proliferation and the induction of four oestrogen-regulated RNAs (pNR-1, pNR-2, pNR-25 and cathepsin D) have been measured in MCF-7 breast cancer cells in phenol red-free culture medium. Tamoxifen and 3-hydroxytamoxifen acted as partial oestrogens to stimulate cell growth and the levels of the pNR-2 and pNR-25 RNAs. They were full oestrogens for the induction of cathepsin D RNA and induced the pNR-1 RNA above the level found in oestrogen-treated cells. N-Desmethyltamoxifen and 4-hydroxytamoxifen behaved like tamoxifen except that N-desmethyltamoxifen did not induce the pNR-2 RNA and was only a partial oestrogen for the induction of cathepsin D RNA, and 4-hydroxytamoxifen did not induce the pNR-2 or pNR-25 RNAs. In the presence of oestradiol, the four anti-oestrogens prevented the stimulation of growth and reduced (pNR-2 and pNR-25) or increased (pNR-1) the RNA levels to those present in MCF-7 cells treated with the anti-oestrogen alone. In contrast, for cathepsin D RNA levels there was a synergistic effect of the anti-oestrogens and oestradiol. The concentration at which each anti-oestrogen was effective was related to its affinity for the oestrogen receptor. Metabolite E was a full oestrogen for the induction of cell proliferation and the oestrogen-regulated RNAs. pNR-25 and pNR-2 RNA levels correlated most closely with effects on cell proliferation. These RNAs are therefore potentially the most useful for predicting the response of breast cancer patients to tamoxifen therapy.
authors.affiliation: University Department of Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: M D
authors.initials: MD
authors.lastname: Johnson
authors.forename: B R
authors.initials: BR
authors.lastname: Westley
authors.forename: F E
authors.initials: FE
authors.lastname: May
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D012334:RNA, Neoplasm / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
chemical_list: D004965:Estrogen Antagonists; D012334:RNA, Neoplasm; D013629:Tamoxifen; C038345:droloxifene; C016601:afimoxifene; D004958:Estradiol; C028787:N-desmethyltamoxifen