INVOLVEMENT OF ESTROGEN RECEPTOR BETA 5 IN THE PROGRESSION OF GLIOMA

Purpose: Emerging evidence suggests a decline of ERβ expression in various peripheral cancers and ERβ has been proposed as a cancer brake that inhibits tumor cell growth and proliferation. Our current study analyzed the expression and function of ERβ in human glioma. Methods: Expression of ERβ isoforms in human glioma was analyzed using western blot, immunohistochemsitry and real-time PCR. ERβ expression regulation was investigated in GBM cell line U87. ERβ isoforms were cloned and stable cells were made to evaluate the effects of ERβ on cell signaling and growth/proliferation of GBM cells. Results: we have identified ERβ5 as the predominant isoform of ERβ in human glioma and its expression was significantly increased in human glioma as compared with non-neoplastic brain tissue. Hypoxia and activation of hypoxia inducible factor (HIF) increased ERβ transcription in U87 cells, suggesting elevated ERβ expression in glioma might be induced by the hypoxic stress in the tumor. Over-expression of either ERβ1 or ERβ5 increased PTEN expression and inhibited activation of the PI3K/AKT/mTOR pathway; ERβ5 also inhibited the MAPK/ERK pathway. In U87 cells, ERβ1 and ERβ5 decreased cell proliferation and decreased cells in the S+G2/M phase. Conclusions: Our findings suggest hypoxia induced ERβ5 expression in glioma as a self-protective mechanism against tumor proliferation and that ERβ5 might serve as a therapeutic target for the treatment of glioma.