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Isolation and functional characterization of a novel endogenous inverse agonist of estrogen related receptors (ERRs) from human pregnancy urine.

Ghanbari, Faegheh; Hebert-Losier, Andrea; Barry, Janelle; Poirier, Donald; Giguere, Vincent; Mader, Sylvie; Philip, Anie.
J Steroid Biochem Mol Biol; 191: 105352, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30954508
Estrogen-receptor related receptors (ERRs) which consists of ERRα, ERRß and ERRγ belong to the orphan nuclear receptor subfamily 3, group B (NR3B) subfamily, and are constitutively active. ERRs have been shown to actively modulate estrogenic responses, and to play an essential role in pregnancy, and are implicated in breast cancer progression. Despite intensive efforts, no endogenous ligand other than the ubiquitous sterol, cholesterol which binds ERRα, has been identified for ERRs so far. The discovery of ligands that bind these orphan receptors will allow the manipulation of this pathway and may lead to novel strategies for the treatment of cancer and other diseases. We previously reported the identification of a novel endogenous estradienolone-like steroid (ED) that is strongly bound to sex hormone binding globulin, in pregnant women. Our recent results show that ED acts as an inverse agonist of ERRα and ERRγ by directly interacting with these receptors, and inhibiting their transcriptional activity. We also demonstrate that ED inhibits the growth of both estrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) breast cancer cells in a dose dependent manner, while of displaying a little effect on normal epithelial breast cells. Furthermore, the anti-mitogenic effect of ED in breast cancer cells is ERRα-dependent. These data suggest that ED-ERR interaction may represent a novel physiologically relevant hormone response pathway in the human. The finding that ED inhibits both ER negative and ER positive breast cancer cell growth may have important implications in pathophysiology breast cancer.
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