Therapeutic Targeting of Ovarian Cancer Stem Cells Using Estrogen Receptor Beta Agonist

Abstract

Ovarian cancer (OCa) is the deadliest gynecologic cancer. Emerging studies suggest ovarian cancer stem cells (OCSCs) contribute to chemotherapy resistance and tumor relapse. Recent studies demonstrated estrogen receptor beta (ERβ) exerts tumor suppressor functions in OCa. However, the status of ERβ expression in OCSCs and the therapeutic utility of the ERβ agonist LY500307 for targeting OCSCs remain unknown. OCSCs were enriched from ES2, OV90, SKOV3, OVSAHO, and A2780 cells using ALDEFLUOR kit. RT-qPCR results showed ERβ, particularly ERβ isoform 1, is highly expressed in OCSCs and that ERβ agonist LY500307 significantly reduced the viability of OCSCs. Treatment of OCSCs with LY500307 significantly reduced sphere formation, self-renewal, and invasion, while also promoting apoptosis and G2/M cell cycle arrest. Mechanistic studies using RNA-seq analysis demonstrated that LY500307 treatment resulted in modulation of pathways related to cell cycle and apoptosis. Western blot and RT-qPCR assays demonstrated the upregulation of apoptosis and cell cycle arrest genes such as FDXR, p21/CDKN1A, cleaved PARP, and caspase 3, and the downregulation of stemness markers SOX2, Oct4, and Nanog. Importantly, treatment of LY500307 significantly attenuated the tumor-initiating capacity of OCSCs in orthotopic OCa murine xenograft models. Our results demonstrate that ERβ agonist LY500307 is highly efficacious in reducing the stemness and promoting apoptosis of OCSCs and shows significant promise as a novel therapeutic agent in treating OCa.

Whole-exome mutational landscape and molecular marker study in mucinous and clear cell ovarian cancer cell lines 3AO and ES2

“…It was first reported that CCDC170 copy number variation can reduce its expression, thereby affecting the overall survival of patients with ovarian cancer, and it is a pathogenic mutation of ovarian cancer. At present, agonists such as luteinizing hormone releasing hormone, gonadotropin-releasing hormone and natural estrogen receptor β have shown beneficial effects on the treatment of ovarian cancer [57][58][59]. As a newly discovered downregulated molecular target of ovarian cancer, CCDC170 can provide a new direction for the development of agonists to reverse the treatment of ovarian cancer.…”

Estrogen Signals through ERβ in Breast Cancer; What We Have Learned since the Discovery of the Receptor

“…In addition to IBC, ERβ was also found to be enriched in ovarian cancer stem cells (OVSC), and treatment with LY500307 reduced their stemness and induced apoptosis [114]. Treatment with LY500307 also significantly impaired the tumor-initiating potential of OVSCs in orthotopically implanted xenograft models [114]. Similarly, glioblastomas (GBM) express ERβ, and treatment of GBM cells with this selective agonist reduced proliferation and enhanced apoptosis in vitro (Figure 4C).…”

“…Beyond TNBC, activating tumor-endogenous ERβ by treating mice bearing orthotopically implanted inflammatory breast cancer tumors with LY500307 led to reduced lung metastasis (Figure 4B) [65]. In addition to IBC, ERβ was also found to be enriched in ovarian cancer stem cells (OVSC), and treatment with LY500307 reduced their stemness and induced apoptosis [114]. Treatment with LY500307 also significantly impaired the tumor-initiating potential of OVSCs in orthotopically implanted xenograft models [114].…”

Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

“…ERβ forms homodimers or heterodimers with ERα. The receptor has tumor-suppressive and antiproliferative properties that compete with the functions of ERα in the reproductive system [ 34 ].…”