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Differential Effects of Estrogen Receptor ? Isoforms on Glioblastoma Progression.


ABSTRACT: The estrogen receptor ? (ER?) functions as a tumor suppressor in glioblastoma (GBM) cells. However, the in vivo significance of endogenous ER? and the roles of its isoforms in GBM are incompletely understood. Using ER? isoform-specific PCR screening, we found that GBM cells predominantly express ER?1 and ER?5, along with low levels of ER?2 and ER?4. We observed greater ER?5 expression in higher grades of glioma than in lower grades. In CRISPR-based ER? knockout (KO) cells and ER? KO cells uniquely expressing ER?1 or ER?5 only, ER?1 significantly reduced proliferation. Compared with parental GBM cells, ER? KO cells exhibited high migratory and invasive potentials, and reexpression of ER?1 resulted in the reduction of this phenotype. Interestingly, ER?5 expression increased foci formation and anchorage-independent growth of NIH3T3 cells and increased motile structure formation, including filopodia and ruffles in GBM cells. Only ER?1-expressing tumors resulted in longer mouse survival. RNA-Seq analysis revealed unique pathways modulated by ER?1 and ER?5. Compared with ER? KO cells, ER?1 cells exhibited lower activation of mTOR signaling molecules, including p-mTOR, p-S6K, and p-S6, and ER?5-expressing cells had enhanced mTOR downstream signaling. Unique proteins including several that function as regulators of mTOR, immunomodulatory, and apoptosis pathways bound to ER?1 and ER?5 isoforms. Our work confirms the tumor-suppressive potential of ER?1 and reveals the acquired oncogenic ability of ER?5 in GBM cells. ER? isoform status and their unique interactions with oncogenic pathways may have important implications in GBM progression.Significance: These findings suggest that only ER? isoform 1 has tumor suppressor function in GBM and that ER? isoform switching contributes to GBM progression. Cancer Res; 78(12); 3176-89. ©2018 AACR.

SUBMITTER: Liu J 

PROVIDER: S-EPMC6004261 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Differential Effects of Estrogen Receptor β Isoforms on Glioblastoma Progression.

Liu Jinyou J   Sareddy Gangadhara R GR   Zhou Mei M   Viswanadhapalli Suryavathi S   Li Xiaonan X   Lai Zhao Z   Tekmal Rajeshwar R RR   Brenner Andrew A   Vadlamudi Ratna K RK  

Cancer research 20180416 12


The estrogen receptor β (ERβ) functions as a tumor suppressor in glioblastoma (GBM) cells. However, the <i>in vivo</i> significance of endogenous ERβ and the roles of its isoforms in GBM are incompletely understood. Using ERβ isoform-specific PCR screening, we found that GBM cells predominantly express ERβ1 and ERβ5, along with low levels of ERβ2 and ERβ4. We observed greater ERβ5 expression in higher grades of glioma than in lower grades. In CRISPR-based ERβ knockout (KO) cells and ERβ KO cells  ...[more]

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