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

Abstract

Epithelial ovarian cancer is the most lethal malignancy of the female reproductive tract. A healthy ovary expresses both Estrogen Receptor a (ERa) and b (ERb). Given that ERa is generally considered to promote cell survival and proliferation, thereby, enhancing tumor growth, while ERb shows a protective effect against the development and progression of tumors, the activation of ERb by its agonists could be therapeutically beneficial for ovarian cancer. Here, we demonstrate that the activation of ERb using a newly developed ERb 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 ERb 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.

17β-hydroxysteroid dehydrogenase type 1 improves survival in serous epithelial ovarian tumors

“…In addition, progesterone in vitro reduces cell number and increases apoptosis in ovarian cancer cells ( 35 , 36 ). There is also a need to consider the expression of ERβ in tumor cells, as its presence has been proposed as tumor suppressor by reducing cell cycle-related proteins and inhibiting epithelial-to-mesenchymal transition in ovarian cancer cell lines ( 37 , 38 ). Interestingly, the improved survival associated with 17β-HSD1 presence is observed in serous tumors compared to nonserous tumors.…”

ALDH1A1 promotes PARP inhibitor resistance by enhancing retinoic acid receptor-mediated DNA polymerase θ expression

“…Written informed consent was obtained from all human donors for the use of their tissues. Organoid cultures were established from these tumor tissues as described previously 50 . Organoids were seeded at 1 × 10 4 cells/well in 75% Matrigel in a 96-well plate and treated with different concentrations of olaparib and NCT-505 separately or in combination for 7 days.…”

Chemotherapeutic Potential of AgNP Orchestrated Semecarpus anacardium Nut Extracts Against Ovarian Cancer Cell Line, PA-1

“…In recent years, ovarian cancer (OC), the seventh most common malignancy in women globally, has become one of the most serious diseases [12]. Epithelial ovarian carcinoma constitutes one of the most dangerous malignant types among women [43][44][45]. Family history, age, reproductive history, breast cancer, hormone therapy, obesity, gynecologic surgery, and human papillomavirus are the key risk factors for ovarian cancer [13].…”