Abstract 606: Therapeutic efficacy of ERβ agonists on ovarian cancer
Authors: Sareddy Gangadhara Reddy , Chavez Javier E. , Salazar Humberto , Mann Monica , Hernandez Jocelyn , Krishnan Samaya Rajeshwari , Kost Edward , Tekmal Rajeshwar Rao , Vadlamudi Ratna K. 
Published: May 2015

Abstract
Ovarian cancer (OC) is the deadliest of all gynecologic cancers in the United States. Despite success with initial chemotherapy, 70% of patients relapse with incurable disease. Development of chemotherapy resistance is the main factor for poor long-term survival in OC. OC stem cells are implicated in tumor initiation and therapy resistance and their elimination is critical for the development of efficient therapeutic strategies. The biological effects of estrogens are mediated through their cognate receptors: estrogen receptor alpha (ERα) and ER beta (ERβ). Emerging evidence suggests that OC cells express ERβ that functions as a tumor suppressor; however, the clinical utility of ERβ agonists in OC remains elusive. Here, we have tested the utility of ERβ to inhibit OC progression by employing ERβ specific agonists. We have used three different ERβ agonists: liquiritigenin (LIQ) isolated from the plant Glycyrrhiza uralensis, S-equol from soy isoflavone daidzein, and the synthetic compound LY500307 (Eli Lilly). Western analysis revealed detectable expression of ERβ in all OC models tested (SKOV3, BG1 and OVCAR3). Using ERβ reporter gene assay and ERβ specific target gene expression, we confirmed functionality of the ERβ pathway in OC cells. All three ERβ ligands showed significant growth inhibition in MTT and colony formation assays, and ERβ agonists promoted apoptosis. Treatment with ERβ agonists significantly upregulated the expression of ERβ via autocrine signaling. Mechanistic studies revealed ERβ mediated non-classical signaling via AP1 and SP1 as playing a critical role in ERβ mediated tumor suppression. Of the three ligands tested, LY500307 showed more potent growth inhibitory activity (IC50: 3μM). ERβ knockdown using shRNA significantly reduced the ERβ agonist mediated growth inhibition. Interestingly, we found that OC stem cells express ERβ and ERβ agonists significantly decrease the sphere formation by OC stem cells. Additional assays revealed that ERβ agonists reduced the stemness of OC stem cells and enhanced their sensitivity to chemotherapy. Accordingly, ERβ agonists significantly reduced the growth of chemotherapy resistant ovarian cancer model cells (cisplatin-resistant ES2, paclitaxel resistant SKOV-3TR cells) and sensitized them to apoptosis. Collectively, our findings show that ERβ agonists have the potential to significantly inhibit ovarian cancer cell growth and reduce stemness; therefore, ERβ agonists represent novel therapeutic agents for the management of ovarian cancer.
Citation Format: Gangadhara Reddy Sareddy, Javier E. Chavez, Humberto Salazar, Monica Mann, Jocelyn Hernandez, Samaya Rajeshwari Krishnan, Edward Kost, Rajeshwar Rao Tekmal, Ratna K. Vadlamudi. Therapeutic efficacy of ERβ agonists on ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 606. doi:10.1158/1538-7445.AM2014-606