UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Estrogen and other nuclear hormones bind to their receptors, which are tethered to the promoter of target genes, and allow the receptors to stimulate gene expression by recruiting coactivator proteins. Tamoxifen and other antiestrogens also bind to the estrogen receptor but prevent coactivator recruitment. Through both genetic and structural analysis and in concert with colleagues at UCSF, USC, and the University of Chicago, we found that the coactivator proteins recognize a hydrophobic cleft on the surface of the hormone-bound estrogen and thyroid hormone receptors. Three leucines of the coactivator Nuclear Receptor Box (LXXLL) project into the cleft and couple the proteins together. Tamoxifen prevents coactivator recruitment by displacing part of the estrogen receptor, Helix 12, into the hydrophobic cleft, and this blocks access of the coactivator.

Estrogen receptors activate two entirely different sorts of target genes, some with classical estrogen response elements (EREs) and some with AP-1/CRE elements. We found that tamoxifen mimics estrogen and stimulates the AP-1/CRE regulated target genes in uterine cells, whose growth is stimulated by tamoxifen, but not in breast cancer cells, whose growth is inhibited by tamoxifen. We were the first to propose that this action of tamoxifen is responsible for its estrogen-like effects on proliferation, which is now a classical concept in the field, and recently confirmed in tamoxifen-resistant breast cancer cells that tamoxifen stimulates proliferation. More recently, we have shown that newer antiestrogens, such as raloxifene, which, unlike tamoxifen, do not stimulate uterine growth, are unable to activate the AP-1/CRE target genes in uterine cells, an inability we traced to their ability to promote association of the estrogen receptor with co-repressors.

A second estrogen receptor, ER beta, has actions that oppose that of ER alpha at the AP-1/CRE type of target genes, suggesting a potential for ER beta to inhibit the pro-proliferative action of ER alpha. We were the first to show differential ligand activation of estrogen receptors ER alpha and ER beta at AP1 sites in which ER beta inhibits in the presence of estrogen and activates in the presence of antiestrogens. More recently, we showed that ER beta can oppose and block ER alpha's action at the cyclin D1 gene an important mediator of the pro-proliferative actions of ER alpha.

Selected References

Liu MM, Albanese C, Anderson CM, Hilty K, Webb P, Uht RM, Price RH Jr, Pestell RG, Kushner PJ. Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. J Biol Chem. 2002 Jul 5;277(27):24353-60.

Webb P, Nguyen P, Kushner PJ. Differential SERM effects on corepressor binding dictate ERalpha activity in vivo. J Biol Chem. 2003 Feb 28;278(9):6912-20.

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