Unliganded estrogen receptor-beta regulation of genes is inhibited by tamoxifen.
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.
Levy
Nitzan
N
Department of Obstetrics, Gynecology and Reproductive , University of California, San Francisco, CA, USA.
Paruthiyil
Sreenivasan
S
Zhao
Xiaoyue
X
Vivar
Omar I
OI
Saunier
Elise F
EF
Griffin
Chandi
C
Tagliaferri
Mary
M
Cohen
Isaac
I
Speed
Terence P
TP
Leitman
Dale C
DC
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*
D004965:Estrogen Antagonists; D047629:Estrogen Receptor beta; C527062:KLRC3 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D013629:Tamoxifen