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The tamoxifen-responsive estrogen receptor alpha mutant D351Y shows reduced tamoxifen-dependent interaction with
1Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0034, Japan.
Abstract:
The effects of estrogen and anti-estrogen are mediated through the estrogen receptors ERalpha and beta, which function as ligand-induced transcriptional factors. The nonsteroidal anti-estrogen tamoxifen is the most commonly used endocrine in the treatment of all stages of breast cancer in both pre- and postmenopausal women. Several lines of evidence have indicated that tamoxifen promotes association between ERalpha and corepressors N-CoR or silencing mediator for retinoid and thyroid hormone receptor (SMRT). Our results indicate that N-CoR/SMRT recognize and interact with helices H3 and H5 of the ERalpha ligand-binding domain in a 4-hydroxy tamoxifen-dependent manner. The mutant ERalpha(D351Y), derived from a tamoxifen-stimulated tumor and containing an amino acid substitution at position 351 within H3, showed reduced interaction with N-CoR/SMRT and high tamoxifen-induced activation function-1 (AF-1) activity. While the estradiol-dependent transcriptional activity of ERalpha(D351Y) was almost equal to that of wild-type ERalpha, the mutant exhibited higher levels of transcriptional activity in the presence of both E2 and 4-hydroxy tamoxifen compared with wild-type ERalpha. These results may explain the observation that the growth of tumor cells expressing ERalpha(D351Y) can be stimulated by tamoxifen, E2, or both.
Insights
Tamoxifen, a breast cancer drug, interacts with estrogen receptor alpha (ERalpha). A specific mutation (ERalpha(D351Y)) reduces corepressor binding, leading to increased tamoxifen-driven activity and potential tumor growth stimulation.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- Estrogen receptors (ERalpha and ERbeta) mediate estrogen and anti-estrogen effects as ligand-induced transcriptional factors.
- Tamoxifen is a widely used nonsteroidal anti-estrogen for breast cancer treatment.
- Tamoxifen is known to promote the association of ERalpha with corepressors N-CoR and SMRT.
Purpose of the Study:
- To investigate the interaction between ERalpha and corepressors N-CoR/SMRT.
- To characterize the functional consequences of a specific ERalpha mutation (D351Y) found in tamoxifen-stimulated tumors.
Main Methods:
- Investigated the interaction of N-CoR/SMRT with ERalpha ligand-binding domain helices (H3 and H5) in a 4-hydroxy tamoxifen-dependent manner.
- Utilized a mutant ERalpha (ERalpha(D351Y)) with an amino acid substitution in helix H3.
- Assessed transcriptional activity of wild-type and mutant ERalpha in the presence of estradiol (E2) and/or 4-hydroxy tamoxifen.
Main Results:
- N-CoR/SMRT interact with ERalpha helices H3 and H5 in a 4-hydroxy tamoxifen-dependent manner.
- The ERalpha(D351Y) mutant showed reduced interaction with N-CoR/SMRT.
- ERalpha(D351Y) exhibited significantly higher tamoxifen-induced activation function-1 (AF-1) activity compared to wild-type ERalpha.
- Mutant ERalpha(D351Y) displayed increased transcriptional activity with both estradiol and 4-hydroxy tamoxifen compared to wild-type ERalpha.
Conclusions:
- The D351Y mutation in ERalpha disrupts corepressor binding, leading to enhanced ERalpha activity.
- This enhanced activity, particularly in the presence of tamoxifen and estradiol, may explain tamoxifen-stimulated tumor growth in cells expressing ERalpha(D351Y).
- Findings provide insight into mechanisms of endocrine resistance in breast cancer.