Therapeutic Significance of Estrogen Receptor β Agonists in Gliomas

Abstract

Gliomas are the most common and devastating central nervous system neoplasms. A gender bias exists in their development: females are at lower risk than males, implicating estrogen-mediated protective effects. Estrogen functions are mediated by two ER subtypes: ERα, that functions as tumor promoter and ERβ that function as tumor suppressor. We examined the potential use of ERβ agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ERβ with little or no ERα. Treatment of glioma cells with ERβ agonists resulted in significant decrease in proliferation. IHC analysis of tumor tissues revealed that ERβ expression is down regulated in high-grade gliomas. We found that ERβ agonists promote both expression and tumor suppressive functions of ERβ in glioma cells. Liquiritigenin, a plant-derived ERβ agonist significantly reduced in vivo tumor growth in a xenograft model. Compared to control mice, animals treated with liquiritigenin had greater than 50% reduction in tumor volume and size. IHC analysis of tumors revealed a significant increase in the nuclear ERβ expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ERβ signaling has a tumor suppressive function in gliomas. Since ERβ agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ERβ agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in glioma patients.

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

“…In breast cancer, ERb agonist was found to arrest angiogenesis and tumor growth in mouse xenograft models . Selective ERb agonists have also been shown to reduce hepatoma, gliomas, and medulloblastoma growth (Zhou et al 2010, Mancuso et al 2011, Sareddy et al 2012. Each cell type has different cofactors and coregulators and the effect of receptor activation might be different and hence tissuespecific.…”

Sexual dimorphism in cancer

“…ERβ function is required for normal lung and colon morphogenesis 24,25 and its activation exerts beneficial consequences in experimental models of colon 95 , glioma 96 , mesothelioma 97 , renal cell carcinoma (RCC) 98 and T cell lymphoma 99 .…”

Potential benefits of adlay on hyperandrogenism in human chorionic gonadotropin-treated theca cells and a rodent model of polycystic ovary syndrome

“…Licorice have been claimed to possess cholesterol-lowering activity (Chen, Ma, Liang, Peng, & Zuo, 2011). Liquiritigenin in licorice is an estrogen receptor-β agonist that can inhibit the growth of breast cancer cells (Sareddy et al, 2012). Isoliquiritigenin is also an active substance in licorice; it inhibits the distal metastasis of MDA-MB-231 cells (Wang et al, 2013).…”