Molecular Endocrinology, Vol 8, 1397-1406, Copyright © 1994 by Endocrine Society

ARTICLES

Activation of transcriptionally inactive human estrogen receptors by cyclic adenosine 3',5'-monophosphate and ligands including antiestrogens

BA Ince, MM Montano and BS Katzenellenbogen
Department of Physiology and Biophysics, University of Illinois, Urbana 61801.

We show that some transcriptionally inactive human estrogen receptor (ER) mutants can be activated by 17 beta-estradiol (E2), and sometimes by antiestrogens, in the presence of elevated levels of intracellular cAMP. ER-deficient Chinese hamster ovary or 3T3 mouse fibroblast cells were transfected with mutant ERs (the point mutant L540Q, the frameshift mutant S554fs, or the carboxy-terminal truncated receptor ER1-530) and various estrogen response element-containing reporter genes. Individual treatments with E2, the antiestrogens trans- hydroxytamoxifen and ICI 164,384, or with 3-isobutyl-1-methyl-xanthine plus cholera toxin (IBMX plus CT) which raise intracellular cAMP, generally do not activate the mutant receptors. However, cotreatment with IBMX/CT and one of the three ligands (E2, trans-hydroxytamoxifen, or ICI164,384) results in the unexpected recovery of strong activation of the L540Q or S554fs receptors, the magnitude of which is dependent upon promoter- and cell-contexts. Unlike L540Q and S554fs, the transcriptionally inactive ER1-530 is not activated by any combination of ligands and IBMX/CT. These data demonstrate that some ER mutants that form transcriptionally nonproductive ER-E2 complexes can be successfully activated by the combination of an agonist or antagonist ligand and an agent thought to act via phosphorylation pathways. Also highlighted is the promoter- and cell-specific nature of the transcriptional response to different ligand-ER complexes. Lastly, the enhanced transcriptional activity of wild type ER and some ER mutants in the presence of antiestrogens and elevated intracellular cAMP may provide a partial explanation of the ability of some estrogen-dependent human breast tumors to resist antiestrogen therapies currently employed.

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