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Glioblastoma, the most common form of primary malignant brain tumor, is known for its high incidence rate and low response to therapy.Despite conventional treatments including surgical resection, radiation therapy and chemotherapy, frequent tumor recurrence has resulted in poor prognosis within a shortperiod.Recent studies have indicated that Tamoxifen (TAM), a potent estrogen receptor (ER) antagonist derived from nonsteroid triphenylethylene, which has been extensively used into the clinical therapy of ERpositive ornegative tumors, can offer some benefits to the treatment of glioblastoma via sensitizing the tumor cells to radiotherapy and inhibiting cell proliferation.Although accumulating evidence has confirmed that adjuvant TAM treatment can sensitize glioblastoma cells to radiotherapy and inhibit their proliferation, TAM is not suitable for all types of glioblastoma cells, and longterm TAM usage would lead to resistance against the drug.Therefore, understanding the underlying molecular mechanism of TAM resistance is necessary for improving the efficiency of clinical therapy and the quality of life for patients suffering from glioblastomas.In this study, the significance of ERα36 in TAM resistance in glioblastoma cells was examined.First, analysis of ERo36 expression in the glioblastoma cell lines C6, U87MG and U251showed that ERα36 was anchored to the cytoplasmic membrane of these cells via Caveolin1.Subsequent experiments investigating the mechanism of TAMinduced inhibition of U87MG cell growth showed that it exerted this effect through inducing apoptosis via downregulating the expression of Survivin and upregulating the expression of Caspase3.Furthermore, TAM also arrested the cell cycle at the Sphase.However, preconditioning U87MG cells with the ERα36specific agonist IC 162 neutralized, whereas knockdown of ERα36 by RNAi enhanced TAMinduced inhibition of cell growth, suggesting that resistance to TAM involved the action of ERα36, which probably acted as a negative regulator of TAMinduced inhibition of glioblastoma cell growth.These findings provided novel insight into the basis of TAM resistance in glioblastoma therapy, and further study is underway to reveal more about this special molecular mechanism of ERα36mediated TAM resistance.