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

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 (ER beta) exerts tumor suppressor functions in OCa. However, the status of ER beta expression in OCSCs and the therapeutic utility of the ER beta 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 ER beta, particularly ER beta isoform 1, is highly expressed in OCSCs and that ER beta 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 ER beta 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.

Automated summary

This study found that ovarian cancer stem cells (OCSCs) highly express ER beta, and the ER beta agonist LY500307 can significantly reduce the viability of OCSCs, inhibit sphere formation, self-renewal, and invasion, and promote apoptosis and G2/M cell cycle arrest. Further investigation revealed that LY500307 exerts its effects by modulating pathways related to cell cycle and apoptosis. Additionally, LY500307 treatment attenuated the tumor-initiating capacity of OCSCs in mice. These findings demonstrate that LY500307 is a promising novel therapeutic agent for ovarian cancer.