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

Area of Science:

• Gynecologic Oncology
• Cancer Stem Cell Biology
• Endocrinology

Background:

• Ovarian cancer (OCa) is a leading cause of gynecologic cancer mortality.
• Ovarian cancer stem cells (OCSCs) are implicated in chemotherapy resistance and tumor recurrence.
• Estrogen receptor beta (ERβ) has demonstrated tumor suppressor roles in OCa.

Purpose of the Study:

• To investigate ERβ expression in OCSCs.
• To evaluate the therapeutic potential of the ERβ agonist LY500307 against OCSCs.
• To elucidate the mechanisms by which LY500307 affects OCSCs.

Main Methods:

• OCSCs were enriched using the ALDEFLUOR kit from various OCa cell lines.
• ERβ expression, OCSC viability, sphere formation, self-renewal, invasion, apoptosis, and cell cycle arrest were assessed.
• RNA-seq, Western blot, and RT-qPCR were employed for mechanistic studies.
• Efficacy was evaluated in orthotopic OCa murine xenograft models.

Main Results:

• ERβ, particularly isoform 1, was highly expressed in OCSCs.
• LY500307 significantly reduced OCSC viability, sphere formation, self-renewal, and invasion.
• LY500307 induced apoptosis and G2/M cell cycle arrest, modulating relevant gene pathways.
• LY500307 treatment downregulated stemness markers (SOX2, Oct4, Nanog) and upregulated apoptosis/cell cycle arrest genes (FDXR, p21/CDKN1A, cleaved PARP, caspase 3).
• LY500307 attenuated OCSC tumor-initiating capacity in vivo.

Conclusions:

• ERβ is expressed in OCSCs and can be targeted by the agonist LY500307.
• LY500307 effectively reduces OCSC stemness properties and promotes apoptosis.
• LY500307 demonstrates significant therapeutic promise for ovarian cancer treatment by targeting OCSCs.