A Novel Estrogen Receptor β Agonist Diminishes Ovarian Cancer Stem Cells via Suppressing the Epithelial-to-Mesenchymal Transition

SIMPLE SUMMARY: Estrogen receptors α (ERα) and β (ERβ) show distinct contributions to tumor initiation and progression. Given that ERβ mainly functions as a “tumor suppressor”, activation of ERβ using its specific agonist should be able to inhibit tumor progression. In this study, we show that a newly developed ERβ agonist, OSU-ERb-12, can not only impede ovarian cancer cell expansion and tumor growth but also reduce the cancer stem cell (CSC) population. OSU-ERb-12 could inhibit epithelial-to-mesenchymal transition (EMT) in ovarian cancer cells by increasing Snail expression, thereby, blocking EMT-mediated cancer cell dedifferentiation. We also found that OSU-ERb-12 inhibits ovarian cancer expansion in an ERα-independent manner while limiting the CSC population in an ERα-dependent manner. Taken together, our data suggest that the newly developed ERβ agonist OSU-ERb-12 can be used not only to hinder tumor growth but also has the potential to prevent tumor relapse and metastasis by depleting CSCs. ABSTRACT: Epithelial ovarian cancer is the most lethal malignancy of the female reproductive tract. A healthy ovary expresses both Estrogen Receptor α (ERα) and β (ERβ). Given that ERα is generally considered to promote cell survival and proliferation, thereby, enhancing tumor growth, while ERβ shows a protective effect against the development and progression of tumors, the activation of ERβ by its agonists could be therapeutically beneficial for ovarian cancer. Here, we demonstrate that the activation of ERβ using a newly developed ERβ agonist, OSU-ERb-12, can impede ovarian cancer cell expansion and tumor growth in an ERα-independent manner. More interestingly, we found that OSU-ERb-12 also reduces the cancer stem cell (CSC) population in ovarian cancer by compromising non-CSC-to-CSC conversion. Mechanistically, we revealed that OSU-ERb-12 decreased the expression of Snail, a master regulator of the epithelial-to-mesenchymal transition (EMT), which is associated with de novo CSC generation. Given that ERα can mediate EMT and facilitate maintenance of the CSC subpopulation and that OSU-ERb-12 can block the transactivity of ERα, we conclude that OSU-ERb-12 reduces the CSC subpopulation by inhibiting EMT in an ERα-dependent manner. Taken together, our data indicate that the ERβ agonist OSU-ERb-12 could be used to hinder tumor progression and limit the CSC subpopulation with the potential to prevent tumor relapse and metastasis in patients with ovarian cancer.