Emerging evidence suggests a decline of ER beta expression in various peripheral cancers. ER beta has been proposed as a cancer brake that inhibits tumor proliferation. In the current study, we have identified ER beta 5 as the predominant isoform of ER beta 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 (HIE) increased ER beta transcription in U87 cells, suggesting elevated ER beta expression in glioma might be induced by the hypoxic stress in the tumor. Over-expression of either ER beta 1 or ER beta 5 increased PTEN expression and inhibited activation of the PI3K/AKT/mTOR pathway. In addition, ER beta 5 inhibited the MAPK/ERK pathway. In U87 cells, ER beta 1 and ER beta 5 inhibit cell proliferation and reduced cells in the S+G2/M phase. Our findings suggest hypoxia induced ER beta 5 expression in glioma as a self-protective mechanism against tumor proliferation and that ER beta 5 might serve as a therapeutic target for the treatment of glioma. (C) 2013 Elsevier B.V. All rights reserved.