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Agonistic and synergistic activity of tamoxifen in a yeast model system
1Institute for Applied Microbiology, University of the Agricultural Sciences, Vienna, Austria.
Abstract:
The background of agonist/antagonist behaviour of the non-steroidal antiestrogen tamoxifen is still not fully understood. Depending on cell type, its activities range from full agonistic to antagonistic in different tissues. We investigated the transactivational properties of tamoxifen in a basic yeast model system which reconstitutes ligand-dependent human estrogen receptor-alpha (hER alpha) gene activation. Tamoxifen exerted low agonist activity in this system compared to 17 beta-estradiol (E2). Efficiencies and potencies of several isomers were calculated by fitting experimental data with a logistic dose-response function. Cis-, trans- and cis-transtamoxifen and trans-4-hydroxytamoxifen (4-OHT) showed comparable efficiencies and potencies in yeast. When subeffective doses of trans-, cis-/trans-, or trans-4-OH tamoxifen were combined with increasing 17 beta-estradiol concentrations, even a synergistic increase in efficiencies could be observed. Interestingly, the cis-isomer did not show this synergistic effect. Mutation of the N-terminus of the estrogen receptor changed the transactivational behaviour of tamoxifen and abolished the synergistic action with 17 beta-estradiol. Except for 4-OHT, the potencies of the investigated isomers, defined as ligand concentrations with half-maximal response, highly correlated with the binding affinities to hER alpha. Therefore, cis-, trans-, and cis-/trans-tamoxifen could be regarded as full agonists in yeast, while 4-OHT was regarded as a partial antagonist in yeast. Furthermore, these results indicate that the functional difference between trans-tamoxifen and trans-4-OHT is not due to their different affinities for the receptor protein.
Insights
Tamoxifen
Area of Science:
- Endocrinology
- Molecular Biology
- Pharmacology
Background:
- Tamoxifen exhibits variable agonist/antagonist activity depending on cell type and tissue.
- The precise mechanisms underlying tamoxifen's dual behavior remain incompletely understood.
- Investigating tamoxifen's transactivational properties offers insight into estrogen receptor signaling.
Purpose of the Study:
- To investigate the transactivational properties of tamoxifen and its isomers.
- To elucidate the agonist/antagonist behavior of tamoxifen in a yeast model of human estrogen receptor-alpha (hERα) activation.
- To compare the potencies and efficiencies of different tamoxifen isomers and their interactions with 17 beta-estradiol (E2).
Main Methods:
- Utilized a yeast model system for studying ligand-dependent human estrogen receptor-alpha (hERα) gene activation.
- Quantified tamoxifen isomer efficiencies and potencies using logistic dose-response functions.
- Analyzed the synergistic effects of tamoxifen isomers combined with 17 beta-estradiol (E2).
- Investigated the impact of N-terminal estrogen receptor mutations on tamoxifen activity.
Main Results:
- Tamoxifen displayed low agonist activity compared to 17 beta-estradiol (E2) in the yeast model.
- Cis-, trans-, and cis-trans-tamoxifen isomers showed comparable efficiencies and potencies, correlating with binding affinities.
- Trans-tamoxifen isomers, but not the cis-isomer, exhibited synergistic effects with E2.
- N-terminal estrogen receptor mutations altered tamoxifen's transactivational behavior and abolished synergy with E2.
- Trans-4-hydroxytamoxifen (4-OHT) acted as a partial antagonist in yeast, distinct from other isomers.
Conclusions:
- Tamoxifen isomers (cis-, trans-, cis-trans-) function as full agonists in yeast, with potencies linked to binding affinity.
- Trans-4-hydroxytamoxifen (4-OHT) acts as a partial antagonist in yeast.
- The functional differences between trans-tamoxifen and 4-OHT are not solely attributable to receptor binding affinity.
- Synergistic effects observed with E2 highlight the complex modulation of estrogen receptor activity by tamoxifen isomers.