Abstract 4375: Inhibition of triple negative breast cancer cell progression using estrogen related receptor alpha endogenous ligands

Abstract

Abstract Triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is considered to be more metastatic, and has poorer prognosis and higher risk of recurrence than other subtypes of breast cancer. The death rate in patients with TNBC is twice that of ERα positive tumors mainly because there are fewer targeted therapies that treat TNBC patients [1]. Therefore, there is a need to discover new drug-targeted therapy for these patients. Several lines of evidence indicate that estrogen related receptors (ERRs), which belong to the orphan nuclear receptor superfamily, play a crucial role in breast cancer, with ERRα overexpression reportedly leading to adverse clinical outcomes in TNBC patients [2]. Despite intensive efforts, no endogenous ligand has been identified for ERRs so far. The discovery of ligands that bind these receptors may lead to novel strategies for the treatment of TNBC. In this study we show two endogenous ligands of ERRs: 1) estradienolone (ED), a novel endogenous steroid during pregnancy which acts as an inverse agonist of ERRs, 2) cholesterol as an agonist of ERRs. 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 has strong anti-mitogenic properties. 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. In addition, we show that cholesterol binds directly and specifically to ERRα, it increases the transcriptional activity of ERRα in a peroxisome proliferator-activated receptor coactivator-1α (PGC-1) dependent manner. Our finding suggests that cholesterol enhances the interaction of ERRα and its coactivator PGC-1, and this leads to induce the expression of ERRα itself (an specific auto-induction) and the metabolic target genes of ERRα to fuel TNBC cells proliferation and migration. Moreover, our results demonstrates that the effect of cholesterol or lovastatin (a drug known to inhibit cholesterol synthesis) in triple negative breast cancer (MDA-MB 231) requires ERRα. These data suggest that both ED-ERR and cholesterol-ERR interactions may represent novel druggable signaling pathway in TNBC. Citation Format: Faegheh Ghanbari, Sylvie Mader, Anie Philip. Inhibition of triple negative breast cancer cell progression using estrogen related receptor alpha endogenous ligands [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4375.