Preclinical Development Therapeutic Significance of Estrogen Receptor b Agonists in Gliomas

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 estrogen receptor (ER) subtypes: ERa, which functions as tumor promoter, and ERb, which functions as tumor suppressor. We examined the potential use of ERb agonists as a novel therapeutic to curb the growth of gliomas.Western analysis of six gliomamodel cells showed detectable expression of ERb with little or no ERa. Treatment of glioma cells with ERb agonists resulted in significant decrease in proliferation. Immunohistochemical analysis of tumor tissues revealed that ERb expression is downregulated in high-grade gliomas. We found that ERb agonists promote both expression and tumorsuppressive functions of ERb in glioma cells. Liquiritigenin, a plant-derived ERb agonist significantly reduced in vivo tumor growth in a xenograft model. Compared with control mice, animals treated with liquiritigenin hadgreater than 50% reduction in tumor volume and size. Immunohistochemical analysis of tumors revealed a significant increase in the nuclear ERb expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ERb signaling has a tumor-suppressive function in gliomas. Because ERb agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ERb 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.Mol Cancer Ther; 11(5);