Unliganded estrogen receptor-β 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 ERβ inhibits ERα-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 ERβ on gene regulation. Gene expression profiles demonstrated that unliganded ERβ 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 ERβ activates genes and how tamoxifen blocks this effect, we used doxycycline-inducible U2OS-ERβ cells to produce unliganded ERβ. Doxycycline produced a dose-dependent activation of the NKG2E, MSMB and TUB3A genes, which was abolished by tamoxifen. Unliganded ERβ recruitment of SRC-2 to the NKG2E gene was blocked by tamoxifen. Our findings suggest that tamoxifen might exert a negative effect on ERβ expressing tumors due to its antagonistic action on unliganded ERβ.