title: Differential SERM effects on corepressor binding dictate ERalpha activity in vivo.
abstract: Selective estrogen receptor modulators (SERMs) show differential effects upon ERalpha activation function 1 (AF-1). Tamoxifen allows strong ERalpha AF-1 activity, whereas raloxifene allows less and ICI 182,780 (ICI) allows none. Here, we show that blockade of corepressor histone de-acetylase (HDAC) activity reverses the differential inhibitory effect of SERMs upon AF-1 activity in MCF-7 cells. This suggests that differential SERM repression of AF-1 involves HDAC-dependent corepressors. Consistent with this, ICI and raloxifene are more potent than tamoxifen in promoting ERalpha-dependent sequestration of progesterone receptor-associated corepressors. Moreover, ICI and raloxifene are more efficient than tamoxifen in promoting ERalpha binding to the corepressor N-CoR in vivo and in vitro. An ERalpha mutation (537X) that increases N-CoR binding in the presence of all SERMs blocks AF-1 activity. An ERalpha mutation (L379R) that decreases N-CoR binding increases AF-1 activity in the presence of ICI and raloxifene and reverses the effect of the 537X mutation. The 537X and L379R mutations also alter the ligand preference of ERalpha action at AP-1 sites and C3 complement, an action that also involves AF-1. Together, our results suggest that differential SERM effects on corepressor binding can explain differences in SERM effects on ERalpha activity. We propose a model for differential effects of SERMs on N-CoR binding.
authors.affiliation: Diabetes Center and the Department of Medicine, University of California, San Francisco, California 94143, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kushner
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015153:Blotting, Western; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D000077267:Fulvestrant; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011374:Progesterone / Q000494:pharmacology; D011485:Protein Binding; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D000077267:Fulvestrant; D020849:Raloxifene Hydrochloride; D011374:Progesterone; D004958:Estradiol; D008156:Luciferases; D005982:Glutathione Transferase; D006655:Histone Deacetylases