Molecular Determinants for the Tissue Specificity of SERMs

TLDR

Selective estrogen receptor modulators (SERMs) act as estrogen agonists in some tissues and antagonists in others, with tamoxifen’s antiestrogenic effect driving breast cancer therapy while its estrogenic action in the uterus complicates treatment. The study shows that tamoxifen and raloxifene recruit corepressors in mammary cells, whereas tamoxifen uniquely recruits coactivators in endometrial cells, and that high SRC‑1 expression is required for tamoxifen’s estrogenic activity, indicating that tissue‑specific coregulator recruitment dictates SERM responses.

Abstract

Selective estrogen receptor modulators (SERMs) mimic estrogen action in certain tissues while opposing it in others. The therapeutic effectiveness of SERMs such as tamoxifen and raloxifene in breast cancer depends on their antiestrogenic activity. In the uterus, however, tamoxifen is estrogenic. Here, we show that both tamoxifen and raloxifene induce the recruitment of corepressors to target gene promoters in mammary cells. In endometrial cells, tamoxifen, but not raloxifene, acts like estrogen by stimulating the recruitment of coactivators to a subset of genes. The estrogen-like activity of tamoxifen in the uterus requires a high level of steroid receptor coactivator 1 (SRC-1) expression. Thus cell type– and promoter-specific differences in coregulator recruitment determine the cellular response to SERMs.