title: Estrogen-related receptor-alpha antagonist inhibits both estrogen receptor-positive and estrogen receptor-negative breast tumor growth in mouse xenografts.
abstract: Estrogen-related receptors (ERR) are orphan members of the nuclear receptor superfamily most closely related to estrogen receptors (ER). Although ERalpha 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 ERRalpha subtype-specific antagonists have started to emerge. In particular, we recently identified a novel compound, N-[(2Z)-3-(4,5-dihydro-1,3-thiazol-2-yl)-1,3-thiazolidin-2-yl idene]-5H dibenzo[a,d][7]annulen-5-amine (termed compound A) that acts specifically as an ERRalpha antagonist. Here, we show that compound A inhibited cell proliferation in ERalpha-positive (MCF-7 and T47D) and ERalpha-negative (BT-20 and MDA-MD-231) breast cancer cell lines. Furthermore, we report the differential expression of 83 genes involved in ERRalpha 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 ERRalpha signaling in vitro were evaluated and confirmed in vivo by studying uterine gene expression profiles from xenograft mice. These results suggest for the first time that inhibition of ERRalpha signaling via a subtype-specific antagonist may be an effective therapeutic strategy for ER-positive and ER-negative breast cancers.
authors.affiliation: Department of Molecular Endocrinology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chisamore
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Wilkinson
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Flores
authors.forename: J Don
authors.initials: JD
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity / Q000187:drug effects; D053778:Thiazolidines / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D053778:Thiazolidines; D000097983:ERRalpha Estrogen-Related Receptor; C541013:N-(3-(4,5-dihydro-1,3-thiazol-2-yl)-1,3-thiazolidin-2-ylidene)-5H-dibenzo(a,d)(7)annulen-5-amine