Dataset Information

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]

PMID: 29661831

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Project description:Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.

Project description:BackgroundEstrogen promotes breast cancer development and progression mainly through estrogen receptor (ER). However, blockage of estrogen production or action prevents development of and suppresses progression of ER-negative breast cancers. How estrogen promotes ER-negative breast cancer development and progression is poorly understood. We previously discovered that deletion of cell cycle inhibitors p16Ink4a (p16) or p18Ink4c (p18) is required for development of Brca1-deficient basal-like mammary tumors, and that mice lacking p18 develop luminal-type mammary tumors.MethodsA genetic model system with three mouse strains, one that develops ER-positive mammary tumors (p18 single deletion) and the others that develop ER-negative tumors (p16;Brca1 and p18;Brca1 compound deletion), human BRCA1 mutant breast cancer patient-derived xenografts, and human BRCA1-deficient and BRCA1-proficient breast cancer cells were used to determine the role of estrogen in activating epithelial-mesenchymal transition (EMT), stimulating cell proliferation, and promoting ER-negative mammary tumor initiation and metastasis.ResultsEstrogen stimulated the proliferation and tumor-initiating potential of both ER-positive Brca1-proficient and ER-negative Brca1-deficient tumor cells. Estrogen activated EMT in a subset of Brca1-deficient mammary tumor cells that maintained epithelial features, and enhanced the number of cancer stem cells, promoting tumor progression and metastasis. Estrogen activated EMT independent of ER in Brca1-deficient, but not Brca1-proficient, tumor cells. Estrogen activated the AKT pathway in BRCA1-deficient tumor cells independent of ER, and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression.ConclusionsThis study reveals for the first time that estrogen promotes BRCA1-deficient tumor initiation and progression by stimulation of cell proliferation and activation of EMT, which are dependent on AKT activation and independent of ER.

Dataset Information

Differential Effects of Estrogen Receptor ? Isoforms on Glioblastoma Progression.

Publications

Differential Effects of Estrogen Receptor β Isoforms on Glioblastoma Progression.

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