@article{a8187195f15e44d494b0710e8bd251a0,
title = "Activation of estrogen receptor beta signaling reduces stemness of glioma stem cells",
abstract = "Glioblastoma (GBM) is the most common and deadliest tumor of the central nervous system. GBM has poor prognosis and glioma stem cells (GSCs) are implicated in tumor initiation and therapy resistance. Estrogen receptor β (ERβ) is expressed in GBM and exhibit tumor suppressive function. However, the role of ERβ in GSCs and the therapeutic potential of ERβ agonists on GSCs remain largely unknown. Here, we examined whether ERβ modulates GSCs stemness and tested the utility of two ERβ selective agonists (LY500307 and Liquiritigenin) to reduce the stemness of GSCs. The efficacy of ERβ agonists was examined on GSCs isolated from established and patient derived GBMs. Our results suggested that knockout of ERβ increased the proportion of CD133+ and SSEA+ positive GSCs and overexpression of ERβ reduced the proportion of GSCs in GBM cells. Overexpression of ERβ or treatment with ERβ agonists significantly inhibited the GSCs cell viability, neurosphere formation, self-renewal ability, induced the apoptosis and reduced expression of stemness markers in GSCs. RNA sequencing analysis revealed that ERβ agonist modulate pathways related to stemness, differentiation and apoptosis. Mechanistic studies showed that ERβ overexpression or agonist treatment reduced glutamate receptor signaling pathway and induced apoptotic pathways. In orthotopic models, ERβ overexpression or ERβ agonists treatment significantly reduced the GSCs mediated tumor growth and improved the mice overall survival. Immunohistochemical studies demonstrated that ERβ overexpression decreased SOX2 and GRM3 expression and increased expression of GFAP in tumors. These results suggest that ERβ activation could be a promising therapeutic strategy to eradicate GSCs.",
keywords = "estrogen receptor β, gene expression, glioblastoma, glioma stem cells",
author = "Sareddy, {Gangadhara R.} and Pratap, {Uday P.} and Venkata, {Prabhakar Pitta} and Mei Zhou and Salvador Alejo and Suryavathi Viswanadhapalli and Tekmal, {Rajeshwar R.} and Brenner, {Andrew J.} and Vadlamudi, {Ratna K.}",
note = "Funding Information: We thank Jessica Perry (Ob/Gyn, UTHSA) for proofreading this manuscript. This study was supported by NIH‐CA178499 (R.K.V., A.J.B.), Mays Cancer Center Support Grant P30CA054174‐17, American Brain Tumor Association Discovery Grant, Max and Minnie Tomerlin Voelcker Fund Young Investigator Grant (G.R.S.) and NIH South Texas Medical Scientist Training Program (T32GM113898; S.A.). Data generated in the Genome Sequencing Facility was NIH Shared Instrument Grant 1S10OD021805‐01 (S10 grant) and CPRIT Core Facility Award (RP160732). Flow cytometry data was generated in the UT Health San Antonio Flow Cytometry Shared Resource Facility, which is supported by UT Health San Antonio, the Mays Cancer Center P30 Cancer Center Support Grant (NIH‐NCI P30 CA054174) and the National Center for Advancing Translational Sciences, NIH, through grant UL1 TR002645. Funding Information: We thank Jessica Perry (Ob/Gyn, UTHSA) for proofreading this manuscript. This study was supported by NIH-CA178499 (R.K.V., A.J.B.), Mays Cancer Center Support Grant P30CA054174-17, American Brain Tumor Association Discovery Grant, Max and Minnie Tomerlin Voelcker Fund Young Investigator Grant (G.R.S.) and NIH South Texas Medical Scientist Training Program (T32GM113898; S.A.). Data generated in the Genome Sequencing Facility was NIH Shared Instrument Grant 1S10OD021805-01 (S10 grant) and CPRIT Core Facility Award (RP160732). Flow cytometry data was generated in the UT Health San Antonio Flow Cytometry Shared Resource Facility, which is supported by UT Health San Antonio, the Mays Cancer Center P30 Cancer Center Support Grant (NIH-NCI P30 CA054174) and the National Center for Advancing Translational Sciences, NIH, through grant UL1 TR002645. Publisher Copyright: {\textcopyright}AlphaMed Press 2021",
year = "2021",
month = may,
doi = "10.1002/stem.3337",
language = "English (US)",
volume = "39",
pages = "536--550",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press",
number = "5",
}