Effects on Estrogen Receptor Mobility Underlie Antagonist Activity

The estrogen receptor (ER)–targeting agent tamoxifen's active metabolite, 4-OHT, competes with estrogen (E2) for ER's ligand binding domain (LBD), accounting for its therapeutic efficacy in ER⁺ breast cancer. However, 4-OHT also weakly activates ER's N-terminal activation function 1 (AF1) domain, prompting a search for drugs that fully antagonize ER. Conventional wisdom is that ER degradation is a marker of strong antagonism, but Guan, Zhou, and colleagues found that ER degradation was not a reliable predictor in a study of six drugs and drug candidates. The effects of ER antagonists on the LBD did not determine their effects on cell proliferation, consistent with previous observations that the AF1 domain is also important for ER signaling. Each drug or drug candidate predicted to antagonize ER based on ER degradation altered the transcriptional profiles of cancer cell lines in distinct ways, with some activating canonical ER target genes normally induced by E2. In mice, greater transcriptional suppression of ER was associated with more powerful antitumor effects of ER antagonists. Contrary to the hypothesis that the reason the strong ER antagonists fulvestrant and GDC-0927 lack the weak ER-agonist activity of drugs like tamoxifen is that they prevent ER's binding to certain DNA sites, all E2-competitive ligands tested induced ER binding to canonical sites. Hinting at an alternative mechanism, fulvestrant and GDC-0927 binding had only a small impact on chromatin accessibility, whereas E2 and 4-OHT increased accessibility at ER binding sites. Live-cell imaging revealed that only the full antagonists fulvestrant and GDC-0927 uniquely immobilized ER by slowing intranuclear diffusion, and this immobilization dictated antagonism and ER turnover. Collectively, these results not only suggest that ER degradation capability alone should not be used as a proxy for ER antagonism, but also provide proof-of-concept that therapeutics targeting transcription-factor dynamics may be worth investigating.

Guan J, Zhou W, Hafner M, Blake RA, Chalouni C, Chen IP, et al. Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell 20191;78:949–63.e18.

• ©2019 American Association for Cancer Research.