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Antiestrogens: mechanisms and actions in target cells
B S Katzenellenbogen1, M M Montano, P Le Goff
1Department of Physiology and Biophysics, University of Illinois, Urbana 61801, USA.
Abstract:
Antiestrogens, acting via the estrogen receptor (ER) evoke conformational changes in the ER and inhibit the effects of estrogens as well as exerting anti-growth factor activities. Although the binding of estrogens and antiestrogens is mutually competitive, studies with ER mutants indicate that some of the contact sites of estrogens and antiestrogens are likely different. Some mutations in the hormone-binding domain of the ER and deletions of C-terminal regions result in ligand discrimination mutants, i.e. receptors that are differentially altered in their ability to bind and/or mediate the actions of estrogens vs antiestrogens. Studies in a variety of cell lines and with different promoters indicate marked cell context- and promoter-dependence in the actions of antiestrogens and variant ERs. In several cell systems, estrogens and protein kinase activators such as cAMP synergize to enhance the transcriptional activity of the ER in a promoter-specific manner. In addition, cAMP changes the agonist/antagonist balance of tamoxifen-like antiestrogens, increasing their agonistic activity and reducing their efficacy in reversing estrogen actions. Estrogens, and antiestrogens to a lesser extent, as well as protein kinase activators and growth factors increase phosphorylation of the ER and/or proteins involved in the ER-specific response pathway. These changes in phosphorylation alter the biological effectiveness of the ER. Multiple interactions among different cellular signal transduction systems are involved in the regulation of cell proliferation and gene expression by estrogens and antiestrogens.
Insights
Estrogen receptor (ER) activity is complex, influenced by antiestrogens, cell type, and signaling pathways. Phosphorylation and cAMP modify ER function, impacting gene expression and cell growth.
Area of Science:
- Molecular Endocrinology
- Cell Signaling
- Receptor Biology
Background:
- Antiestrogens modulate estrogen receptor (ER) activity by inducing conformational changes and inhibiting estrogen effects.
- ER ligand binding involves competitive interactions, but distinct binding sites for estrogens and antiestrogens exist, as shown by ER mutants.
- Mutations in the ER hormone-binding domain can lead to ligand discrimination mutants, altering the receptor's response to estrogens versus antiestrogens.
Purpose of the Study:
- To investigate the complex mechanisms regulating estrogen receptor (ER) activity by estrogens and antiestrogens.
- To explore the role of cell context, promoter elements, and signaling pathways (e.g., cAMP, phosphorylation) in ER-mediated gene expression.
- To understand how variant ERs and external stimuli modulate the agonist/antagonist balance of antiestrogens.
Main Methods:
- Utilized estrogen receptor (ER) mutants with altered hormone-binding domains and C-terminal regions.
- Conducted studies across various cell lines and with different promoter constructs.
- Investigated the effects of protein kinase activators (e.g., cAMP) and growth factors on ER activity and phosphorylation.
Main Results:
- Demonstrated significant cell context- and promoter-dependent actions of antiestrogens and variant ERs.
- Showed that cAMP can synergize with estrogens to enhance ER transcriptional activity and alter the agonist/antagonist balance of antiestrogens.
- Confirmed that phosphorylation of the ER and associated proteins, influenced by estrogens, antiestrogens, and other signaling molecules, modulates ER biological effectiveness.
Conclusions:
- ER-mediated signaling is highly complex, involving intricate crosstalk between different cellular signal transduction pathways.
- The cellular environment and specific promoter sequences critically influence the biological outcomes of ER activation by estrogens and antiestrogens.
- Understanding these regulatory mechanisms is crucial for deciphering cell proliferation and gene expression control by the ER pathway.