Journal
MOLECULAR CANCER THERAPEUTICS
Volume 11, Issue 5, Pages 1174-1182Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-11-0960
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Funding
- Cancer Center Support grant [P30CA054174]
- [NIH-CA0095681]
- [NS050730]
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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: ER alpha, which functions as tumor promoter, and ER beta, which functions as tumor suppressor. We examined the potential use of ER beta agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ER beta with little or no ER alpha. Treatment of glioma cells with ER beta agonists resulted in significant decrease in proliferation. Immunohistochemical analysis of tumor tissues revealed that ER beta expression is downregulated in high-grade gliomas. We found that ER beta agonists promote both expression and tumor-suppressive functions of ER beta in glioma cells. Liquiritigenin, a plant-derived ER beta agonist significantly reduced in vivo tumor growth in a xenograft model. Compared with control mice, animals treated with liquiritigenin had greater than 50% reduction in tumor volume and size. Immunohistochemical analysis of tumors revealed a significant increase in the nuclear ER beta expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ER beta signaling has a tumor-suppressive function in gliomas. Because ER beta agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ER beta 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); 1174-82. (c) 2012 AACR.
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