Abstract 1712: Estrogen receptor beta signaling sensitizes glioblastoma cells to chemo and radiation therapy
Uday P. PratapGangadhara R. SareddyMengxing LiYiliao LuoMei ZhouSuryavathi ViswanadhapalliRajeshwar R. TekmalAndrew BrennerRatna K. Vadlamudi
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Current treatment options for glioblastoma (GBM) are poor, the mortality rates are very high and therapy resistance is a major clinical problem. Standard treatment consists of surgical resection, external beam radiation therapy, adjuvant chemotherapy with temozolomide (TMZ), and tumor treating fields. Nonetheless, despite a heavy investment in therapy, all patients eventually succumb to their disease. Recent studies suggest that estrogen receptor beta (ERβ) may function as a tumor suppressor in GBM. However, the mechanism(s) by which ERβ contributes to chemo- and radiation therapy response remains unknown. The objective of this study is to examine whether ERβ sensitizes GBM to chemo- and radiation therapy and to understand the mechanistic insights of ERβ mediated tumor suppression in GBM.Methods: To study the functions of endogenous ERβ in GBM cells, we have utilized multiple ERβ overexpressing GBM model (GBM- ERβ) cells using lentiviral transduction. As a second model we have also generated ERβ knockout (ERβKO) cells using CRISPR/Cas9 system, and as a third model we used lentiviral-ERβshRNA transfected primary GBM cells (ERβKD). We then examined the effect of TMZ and radiation on the expression of ERβ using qRT-PCR. The effect of TMZ and radiation on ERβ overexpression and knockout models was examined using MTT cell viability assays. Mechanistic studies were conducted using RNA-seq, HR reporter gene assays, confocal microscopy, western blot, and qRT-PCR analysis. The in vivo role of ERβ on chemo sensitivity of TMZ was studied using orthotopic models of GBM and mouse survival was determined using Kaplan-Meier survival curves.Results: Cell viability and survival assays using multiple established and primary GBM cells demonstrated that ERβ sensitizes GBM cells to DNA damaging agents including TMZ and radiation therapy. qRT-PCR analysis demonstrated that ERβ expression was decreased following chemo- and radiation treatment. Combination analysis of RNA-seq studies using ERβ overexpression, and ERKO models, revealed an alteration in the number of genes involved in DNA recombination and repair, ATM signaling, and cell cycle check point control. Mechanistic studies showed that ERβ plays a significant role in homologous recombination (HR) mediated repair; and ERβ reduced expression and activation of ATM upon DNA damage. Generation of optimal γH2AX foci following TMZ treatment is dependent on the status of ERβ. More importantly, GBM cells expressing ERβ had increased survival when compared to control GBM cells in orthotopic GBM models. ERβ overexpression further enhanced the survival of mice to TMZ therapy in both TMZ sensitive and TMZ resistant GBM models.Conclusion: Our results provided evidence that ERβ is required for optimal chemo- and radiation- induced DNA damage response in GBM cells.Citation Format: Uday P. Pratap, Gangadhara Reddy Sareddy, Mengxing Li, Yiliao Luo, Mei Zhou, Suryavathi Viswanadhapalli, Rajeshwar Rao Tekmal, Andrew Brenner, Ratna K. Vadlamudi. Estrogen receptor beta signaling sensitizes glioblastoma cells to chemo and radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1712.Keywords:
Temozolomide
Estrogen receptor alpha
Estrogen receptor beta
Estrogen receptor beta
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The purpose of this article is to present an assessment of the expression levels of estrogen receptors ER-alpha and ER-beta in malicious tumors of the uterine corpus.Estrogen receptor expression levels were tested using semiquantitative immunohistochemical methods. Paraffin-embedded sections of tissue from the corpus of the uterus from 171 patients were used in the research.Analysis of the relation between ER-beta expression levels and the clinical grade of disease (based on FIGO classification) showed that these parameters are significantly related: p = 0.0099. There were no statistically significant relations between ER-alpha expression levels in tumors or clinical stages of tumors based on the FIGO criteria. The presence of high estrogen receptor beta expression levels is often accompanied by a low estrogen receptor alpha expression level and such arrangements allow the overt biological function of a dominant receptor.The differences in tissue distribution of both estrogen receptors could indicate their different biological roles.
Estrogen receptor alpha
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Progesterone receptor
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GPER
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Estrogen receptors (ER) are members of the nuclear receptor superfamily of ligand-activated transcription factors and mediate the effects of estrogen on target tissues. ERalpha was the first estrogen receptor to be characterized, and ERbeta was identified ten years later. The role of ERbeta in breast cancer pathobiology is largely unknown because specific antibodies have not been available until recently. The purpose of this study was to explore the expression of ERbeta in breast neoplasms and to correlate it with ERalpha and prognosis. ERa and ERbeta expression was monitored immunohistochemically in 59 breast carcinomas. We found no correlation between ERalpha and ERbeta expression, between ERbeta expression and the known prognostic indicators such as tumor size, grade or lymph node status, or between ERbeta expression and survival. Our findings contribute to the better understanding of the role of ERbeta in breast cancer.
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Estrogen receptors are important for the development and maintenance of many different tissues in the body including the breast, uterus, brain and bone. There are two known genes encoding estrogen receptors, Estrogen Receptor alpha (ERα) and Estrogen Receptor beta (ERβ). These receptors are transcription factors with distinct functional domains involved in DNA binding, ligand binding and transcriptional regulation. A novel isoform of human ERβ (ERβ548) which includes an extended amino terminal domain has been identified. Isoform specific antibodies confirm the presence of this receptor in human tissue. Transactivation analysis with different estrogenic ligands indicates that ERβ548 is functionally distinct from previously reported forms of ERβ.
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Abstract Estrogen is of importance for the regulation of adult bone metabolism. The aim of the present study was to determine the role of estrogen receptor-β (ERβ) in vivo on global estrogen-regulated transcriptional activity in bone. The effect of estrogen in bone of ovariectomized mice was determined using microarray analysis including 9400 genes. Most of the genes (95% = 240 genes) that were increased by estrogen in wild-type (WT) mice were also increased by estrogen in ERβ-inactivated mice. Interestingly, the average stimulatory effect of estrogen on the mRNA levels of these genes was 85% higher in ERβ-inactivated than in WT mice, demonstrating that ERβ reduces estrogen receptor-α (ERα)-regulated gene transcription in bone. The average stimulatory effect of estrogen on estrogen-regulated bone genes in ERα-inactivated mice was intermediate between that seen in WT and ERαβ double-inactivated mice. Thus, ERβ inhibits ERα-mediated gene transcription in the presence of ERα, whereas, in the absence of ERα, it can partially replace ERα. In conclusion, our in vivo data indicate that an important physiological role of ERβ is to modulate ERα-mediated gene transcription supporting a “Ying Yang” relationship between ERα and ERβ in mice.
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Estrogen receptors(ERs),belonging to the nuclear receptor superfamily,mainly include ER-α66,ER-α36,ER-α46 and ER-β.Each of them performs specific functions by binding to its ligand such as estrogen.Recently,ER-α36,a novel variant of human estrogen receptor-alpha(ER-α) was identified and cloned.ER-α36 primarily localizes to the plasma membrane and cytoplasma and inhibits the transactivation of both ER-α66 and ER-β.Being predominantly a membrane-based ER,it mediates non-genomic estrogen signaling and involves in resistance to endocrine therapy such as tamoxifen in breast cancer.
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Estrogen receptors are important for the development and maintenance of many different tissues in the body including the breast, uterus, brain and bone. There are two known genes encoding estrogen receptors, Estrogen Receptor alpha (ERα) and Estrogen Receptor beta (ERβ). These receptors are transcription factors with distinct functional domains involved in DNA binding, ligand binding and transcriptional regulation. A novel isoform of human ERβ (ERβ548) which includes an extended amino terminal domain has been identified. Isoform specific antibodies confirm the presence of this receptor in human tissue. Transactivation analysis with different estrogenic ligands indicates that ERβ548 is functionally distinct from previously reported forms of ERβ.
Estrogen receptor beta
Estrogen receptor alpha
PELP-1
Estrogen-related receptor gamma
Estrogen-related receptor alpha
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