Differences between oestrogen receptor activation by oestrogen and antioestrogen

Area of Science:

• Endocrinology
• Molecular Pharmacology
• Cell Biology

Background:

• Triphenylethylene antioestrogens (e.g., tamoxifen) inhibit oestrogen action by binding to the oestrogen receptor (ER).
• The lower biological activity of antioestrogens compared to oestrogens, despite similar binding affinity and nuclear translocation, remains unclear.
• In vivo, antioestrogens are metabolized into more potent hydroxylated forms with high ER affinity.

Purpose of the Study:

• To identify an in vitro criterion for predicting ER ligand agonistic or antagonistic properties.
• To investigate differences in oestrogen receptor (ER) activation by oestrogens and antioestrogens.

Main Methods:

• Stabilized the ER in its native form using molybdate.
• Compared the binding of oestradiol (E2) and 4-hydroxytamoxifen (OHT) to molybdate-treated and activated ER.
• Analyzed ER DNA binding, conformational changes (4S to 5S transformation), and ligand dissociation rates.

Main Results:

• Molybdate inhibited ER DNA binding and 4S to 5S transformation for both E2 and OHT.
• Molybdate increased oestrogen dissociation but not antioestrogen dissociation from the ER.
• Receptor activation by heating decreased E2 dissociation but not OHT dissociation.

Conclusions:

• A distinct difference exists in ER activation triggered by oestrogens versus antioestrogens.
• Antioestrogens likely function as allosteric ligands of the oestrogen receptor (ER).
• This provides a potential in vitro criterion for predicting ER ligand activity.