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Non-competitive steroid inhibition of oestrogen receptor functions
John R Puddefoot1, Stewart Barker, Hilary R Glover
1School of Biological Sciences, Queen Mary, University of London, United Kingdom.
Abstract:
Currently available antioestrogens, such as tamoxifen, are competitive inhibitors that bind to the ligand binding sites of oestrogen receptors, ERalpha and ERbeta. The search for alternative anti-hormone therapies is prompted by the need for drugs that are effective when tumours become tamoxifen resistant. The existence of different receptor isoforms also raise the possibility of improving selectivity. Earlier use of the 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane (4alpha,5- epoxy-17beta-hydroxy-3-oxo-5alpha-androstane-2alpha-carbonitrile), suggested that it had beneficial actions in breast cancer that were only partially attributable to inhibition of steroidogenesis. The present studies on the interactions of trilostane with oestrogen receptors show that it (i) inhibits oestrogen-stimulated proliferation in MCF-7 breast cancer cells, (ii) enhances the affinity of oestradiol binding to ER in rat uteri and specifically increases oestradiol binding to an ERbeta-like isoform, (iii) inhibits ERalpha and ERbeta binding to the classical vitellogenin gene oestrogen response element (ERE) and (iv) inhibits oestrogen-stimulated gene transcription in ERE-linked reporter systems in MCF-7 cells. The results demonstrate a novel, presumably allosteric, mode of antioestrogen action. The beneficial actions of trilostane in breast cancer may be attributed to the combination of this antioestrogen effect with its well documented suppression of steroidogenesis.
Insights
Trilostane, an existing drug, shows novel anti-oestrogen effects by allosterically inhibiting oestrogen receptors (ERalpha and ERbeta). This action, combined with steroidogenesis suppression, may improve breast cancer treatment, especially for tamoxifen-resistant tumors.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Current anti-oestrogen therapies like tamoxifen target oestrogen receptors (ERalpha and ERbeta) but face resistance.
- Tamoxifen resistance in tumors necessitates novel therapeutic strategies and selective ER modulators.
- Trilostane, a steroidogenesis inhibitor, previously showed potential benefits in breast cancer beyond steroid suppression.
Purpose of the Study:
- To investigate the direct interactions of trilostane with oestrogen receptors (ERalpha and ERbeta).
- To elucidate the mechanism of trilostane's anti-oestrogen activity.
- To explore trilostane as a potential therapeutic agent for breast cancer, particularly tamoxifen-resistant types.
Main Methods:
- Assessing trilostane's effect on MCF-7 breast cancer cell proliferation.
- Evaluating trilostane's influence on oestradiol binding affinity to ER in rat uteri.
- Analyzing trilostane's inhibition of ERalpha and ERbeta binding to the oestrogen response element (ERE).
- Measuring trilostane's impact on oestrogen-stimulated gene transcription using reporter systems.
Main Results:
- Trilostane inhibited oestrogen-stimulated proliferation in MCF-7 breast cancer cells.
- Trilostane enhanced oestradiol binding to ER in rat uteri, with specific effects on an ERbeta-like isoform.
- Trilostane demonstrated inhibition of both ERalpha and ERbeta binding to the vitellogenin gene ERE.
- Trilostane suppressed oestrogen-stimulated gene transcription in ERE-linked reporter systems.
Conclusions:
- Trilostane exhibits a novel, likely allosteric, mechanism of anti-oestrogen action.
- The anti-oestrogenic effects of trilostane on ER signaling contribute to its beneficial actions in breast cancer.
- Combining trilostane's anti-oestrogen activity with its steroidogenesis inhibition offers a dual therapeutic approach for breast cancer.