Data from Estrogen-related receptor-α antagonist inhibits both estrogen receptor–positive and estrogen receptor–negative breast tumor growth in mouse xenografts

Abstract

<div>Abstract<p>Estrogen-related receptors (ERR) are orphan members of the nuclear receptor superfamily most closely related to estrogen receptors (ER). Although ERα is a successful target for treating breast cancer, there remains an unmet medical need especially for estrogen-independent breast cancer. Although estradiol is not an ERR ligand, ER and ERR share many commonalities and overlapping signaling pathways. An endogenous ERR ligand has not been identified; however, novel synthetic ERRα subtype–specific antagonists have started to emerge. In particular, we recently identified a novel compound, <i>N</i>-[(2<i>Z</i>)-3-(4,5-dihydro-1,3-thiazol-2-yl)-1,3-thiazolidin-2-yl idene]-5H dibenzo[<i>a,d</i>][7]annulen-5-amine (termed compound A) that acts specifically as an ERRα antagonist. Here, we show that compound A inhibited cell proliferation in ERα-positive (MCF-7 and T47D) and ERα-negative (BT-20 and MDA-MD-231) breast cancer cell lines. Furthermore, we report the differential expression of 83 genes involved in ERRα signaling in MCF-7 and BT-20 breast cancer cell lines. We show that compound A slowed tumor growth in MCF-7 and BT-20 mouse xenograft models, and displayed antagonistic effects on the uterus. Furthermore, a subset of genes involved in ERRα signaling <i>in vitro</i> were evaluated and confirmed <i>in vivo</i> by studying uterine gene expression profiles from xenograft mice. These results suggest for the first time that inhibition of ERRα signaling via a subtype-specific antagonist may be an effective therapeutic strategy for ER-positive and ER-negative breast cancers. [Mol Cancer Ther 2009;8(3):672–81]</p></div>