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Molecular determinants for the tissue specificity of SERMs
1Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Science (New York, N.Y.)
|March 30, 2002
Summary
Selective estrogen receptor modulators (SERMs) have varied effects. Both tamoxifen and raloxifene recruit corepressors in mammary cells, but tamoxifen also recruits coactivators in endometrial cells, depending on SRC-1 levels.
Area of Science:
- Endocrinology
- Molecular Biology
- Pharmacology
Background:
- Selective estrogen receptor modulators (SERMs) exhibit tissue-specific effects, acting as estrogen agonists or antagonists.
- Tamoxifen and raloxifene are key SERMs used in breast cancer therapy, relying on antiestrogenic activity.
- Tamoxifen displays estrogenic effects in the uterus, unlike raloxifene.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the differential cellular responses to SERMs.
- To elucidate the role of coregulator recruitment in mediating SERM activity in different cell types.
- To understand why tamoxifen exhibits estrogenic activity in the uterus.
Main Methods:
- Analysis of coregulator recruitment (coactivators and corepressors) to target gene promoters.
- Comparison of tamoxifen and raloxifene activity in mammary and endometrial cells.
- Assessment of the influence of steroid receptor coactivator 1 (SRC-1) expression levels.
Main Results:
- Both tamoxifen and raloxifene induced corepressor recruitment in mammary cells.
- Tamoxifen, but not raloxifene, stimulated coactivator recruitment to specific genes in endometrial cells.
- The estrogen-like activity of tamoxifen in the uterus was dependent on high SRC-1 expression.
Conclusions:
- Cell type- and promoter-specific coregulator recruitment dictates the cellular response to SERMs.
- Differential recruitment of coactivators and corepressors explains the tissue-specific actions of SERMs.
- SRC-1 expression levels are critical for mediating tamoxifen's estrogenic effects in the endometrium.
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