Related Experiment Videos
Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in
C E Connor1, J D Norris, G Broadwater
1Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
Abstract:
Tamoxifen inhibits estrogen receptor (ER) transcriptional activity by competitively inhibiting estradiol binding and inducing conformational changes in the receptor that may prevent its interaction with coactivators. In bone, the cardiovascular system, and some breast tumors, however, tamoxifen exhibits agonist activity, suggesting that the tamoxifen-ER complex is not recognized identically in all cells. We used phage display to demonstrate that the antiestrogen GW5638 induces a unique structural change in the ER. The biological significance of this conformational change was revealed in studies that demonstrated that tamoxifen-resistant breast tumor explants are not cross-resistant to GW5638. Because of these properties, this drug is currently being developed as a potential therapeutic for tamoxifen-resistant breast cancers.
Insights
The antiestrogen GW5638 induces unique structural changes in the estrogen receptor (ER), offering a potential therapeutic for tamoxifen-resistant breast cancers. This drug is not cross-resistant with tamoxifen in resistant tumors.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Tamoxifen inhibits estrogen receptor (ER) transcriptional activity.
- Tamoxifen exhibits paradoxical agonist activity in certain tissues and breast tumors.
- This suggests differential cellular recognition of the tamoxifen-ER complex.
Purpose of the Study:
- To investigate the structural changes induced by the antiestrogen GW5638 in the ER.
- To determine the biological significance of these conformational changes.
- To evaluate GW5638 as a potential therapeutic for tamoxifen-resistant breast cancers.
Main Methods:
- Phage display was utilized to identify structural changes in the ER induced by GW5638.
- Studies were conducted on tamoxifen-resistant breast tumor explants.
Main Results:
- GW5638 was demonstrated to induce a unique structural change in the ER.
- Tamoxifen-resistant breast tumor explants showed no cross-resistance to GW5638.
- This indicates a distinct mechanism of action compared to tamoxifen.
Conclusions:
- The unique conformational change induced by GW5638 is biologically significant.
- GW5638 represents a promising therapeutic candidate for tamoxifen-resistant breast cancers.
- This drug offers a potential alternative treatment overcoming tamoxifen resistance.