title: Unliganded estrogen receptor-beta regulation of genes is inhibited by tamoxifen.
abstract: Tamoxifen can stimulate the growth of some breast tumors and others can become resistant to tamoxifen. We previously showed that unliganded ERbeta inhibits ERalpha-mediated proliferation of MCF-7 cells. We investigated if tamoxifen might have a potential negative effect on some breast cancer cells by blocking the effects of unliganded ERbeta on gene regulation. Gene expression profiles demonstrated that unliganded ERbeta upregulated 196 genes in MCF-7 cells. Tamoxifen significantly inhibited 73 of these genes by greater than 30%, including several growth-inhibitory genes. To explore the mechanism whereby unliganded ERbeta activates genes and how tamoxifen blocks this effect, we used doxycycline-inducible U2OS-ERbeta cells to produce unliganded ERbeta. Doxycycline produced a dose-dependent activation of the NKG2E, MSMB and TUB3A genes, which was abolished by tamoxifen. Unliganded ERbeta recruitment of SRC-2 to the NKG2E gene was blocked by tamoxifen. Our findings suggest that tamoxifen might exert a negative effect on ERbeta expressing tumors due to its antagonistic action on unliganded ERbeta.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive , University of California, San Francisco, CA, USA.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Levy
authors.forename: Sreenivasan
authors.initials: S
authors.lastname: Paruthiyil
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Zhao
authors.forename: Omar I
authors.initials: OI
authors.lastname: Vivar
authors.forename: Elise F
authors.initials: EF
authors.lastname: Saunier
authors.forename: Chandi
authors.initials: C
authors.lastname: Griffin
authors.forename: Mary
authors.initials: M
authors.lastname: Tagliaferri
authors.forename: Isaac
authors.initials: I
authors.lastname: Cohen
authors.forename: Terence P
authors.initials: TP
authors.lastname: Speed
authors.forename: Dale C
authors.initials: DC
authors.lastname: Leitman
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004965:Estrogen Antagonists; D047629:Estrogen Receptor beta; C527062:KLRC3 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D013629:Tamoxifen