Estrogen Receptor (ER)-α36 Is Involved in Estrogen- and Tamoxifen-Induced Neuroprotective Effects in Ischemic Stroke Models.
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ABSTRACT:
SUBMITTER: Zou W
PROVIDER: S-EPMC4618921 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tamoxifen provided a successful treatment for ER-positive breast cancer for many years. However, HER2 overexpressing breast cancer cells respond poorly to tamoxifen therapy presumably by pass. The molecular mechanisms underlying development of tamoxifen resistance have not been well established. Recently, we reported that breast cancer cells with high levels of ER-α36, a variant of ER-α, were resistant to tamoxifen and knockdown of ER-α36 expression in tamoxifen resistant cells with the shRNA method restored tamoxifen sensitivity, indicating that gained ER-α36 expression is one of the underlying mechanisms of tamoxifen resistance. Here, we found that tamoxifen induced expression of ER-α36-EGFR/HER2 positive regulatory loops and tamoxifen resistant MCF7 cells (MCF7/TAM) expressed enhanced levels of the loops. Disruption of the ER-α36-EGFR/HER2 positive regulatory loops with the dual tyrosine kinase inhibitor Lapatinib or ER-α36 down-regulator Broussoflavonol B in tamoxifen resistant MCF7 cells restored tamoxifen sensitivity. In addition, we also found both Lapatinib and Broussoflavonol B increased the growth inhibitory activity of tamoxifen in tumorsphere cells derived from MCF7/TAM cells. Our results thus demonstrated that elevated expression of the ER-α36-EGFR/HER2 loops is one of the mechanisms by which ER-positive breast cancer cells escape tamoxifen therapy. Our results thus provided a rational to develop novel therapeutic approaches for tamoxifen resistant patients by targeting the ER-α36-EGFR/HER2 loops.
| S-EPMC4396031 | biostudies-literature
Project description:The breast cancer stem cells (BCSC) play important roles in breast cancer occurrence, recurrence and metastasis. However, the role of estrogen signaling, a signaling pathway important in development and progression of breast cancer, in regulation of BCSC has not been well established. Previously, we identified and cloned a variant of estrogen receptor α, ER-α36, with a molecular weight of 36 kDa. ER-α36 lacks both transactivation domains AF-1 and AF-2 of the 66 kDa full-length ER-α (ER-α66) and mediates rapid estrogen signaling to promote proliferation of breast cancer cells. In this study, we aim to investigate the function and the underlying mechanism of ER-α36-mediated rapid estrogen signaling in growth regulation of the ER-positive breast cancer stem/progenitor cells. ER-positive breast cancer cells MCF7 and T47D as well as the variants with different levels of ER-α36 expression were used. The effects of estrogen on BCSC's abilities of growth, self-renewal, differentiation and tumor-seeding were examined using tumorsphere formation, flow cytometry, indirect immunofluorence staining and in vivo xenograft assays. The underlying mechanisms were also studied with Western-blot analysis. We found that 17-β-estradiol (E2β) treatment increased the population of ER-positive breast cancer stem/progenitor cells while failed to do so in the cells with knocked-down levels of ER-α36 expression. Cells with forced expression of recombinant ER-α36, however, responded strongly to E2β treatment by increasing growth in vitro and tumor-seeding efficiency in vivo. The rapid estrogen signaling via the AKT/GSK3β pathway is involved in estrogen-stimulated growth of ER-positive breast cancer stem/progenitor cells. We concluded that ER-α36-mediated rapid estrogen signaling plays an important role in regulation and maintenance of ER-positive breast cancer stem/progenitor cells.
| S-EPMC3928099 | biostudies-literature
Project description:During acute reperfusion, the expression profiles of long noncoding RNAs in adult rats with focal cerebral ischemia undergo broad changes. However, whether long noncoding RNAs are involved in neuroprotective effects following focal ischemic stroke in rats remains unclear. In this study, RNA isolation and library preparation was performed for long noncoding RNA sequencing, followed by determining the coding potential of identified long noncoding RNAs and target gene prediction. Differential expression analysis, long noncoding RNA functional enrichment analysis, and co-expression network analysis were performed comparing ischemic rats with and without ischemic postconditioning rats. Rats were subjected to ischemic postconditioning via the brief and repeated occlusion of the middle cerebral artery or femoral artery. Quantitative real-time reverse transcription-polymerase chain reaction was used to detect the expression levels of differentially expressed long noncoding RNAs after ischemic postconditioning in a rat model of ischemic stroke. The results showed that ischemic postconditioning greatly affected the expression profile of long noncoding RNAs and mRNAs in the brains of rats that underwent ischemic stroke. The predicted target genes of some of the identified long noncoding RNAs (cis targets) were related to the cellular response to ischemia and stress, cytokine signal transduction, inflammation, and apoptosis signal transduction pathways. In addition, 15 significantly differentially expressed long noncoding RNAs were identified in the brains of rats subjected to ischemic postconditioning. Nine candidate long noncoding RNAs that may be related to ischemic postconditioning were identified by a long noncoding RNA expression profile and long noncoding RNA-mRNA co-expression network analysis. Expression levels were verified by quantitative real-time reverse transcription-polymerase chain reaction. These results suggested that the identified long noncoding RNAs may be involved in the neuroprotective effects associated with ischemic postconditioning following ischemic stroke. The experimental animal procedures were approved by the Animal Experiment Ethics Committee of Kunming Medical University (approval No. KMMU2018018) in January 2018.
| S-EPMC8643058 | biostudies-literature
Project description:ObjectivesEstrogen is proven to promote the malignant behaviors of many cancers via its receptors. Estrogen receptor alfa 36 (ER-α36) is a newly identified isoform of estrogen receptor alfa (ER-α), the role of ER-α36 in regulating the effects of estrogen and its potential impact on human cervical cancer is poorly understood.MethodsImmunohistochemistry staining was used to evaluate the expression of ER-α36, estrogen receptor alfa 66 (ER-α66) and their prognostic values in cervical cancer. The effects of ER-α36 and ER-α66 on the proliferation and metastasis of cervical cancer were measured in vitro. A xenograft tumor assay was used to study the tumorigenesis role of ER-α36 in vivo. Furthermore, the functional gene at the downstream of ER-α36 was obtained via next-generation sequencing, and the biological functions of high mobility group A2 (HMGA2) in cervical cancer cells were investigated in vitro.ResultsER-α36 was over-expressed in cervical cancer tissues and elevated ER-α36 expression was associated with poor prognosis in cervical cancer patients. High expression of ER-α36 promoted the proliferation, invasion and metastasis of cervical cancer cells mediated by estrogen, while silencing ER-α36 had the opposite effects. Further research showed that HMGA2 was a downstream target of ER-α36 in cervical cancer cells. The oncogenic effect of ER-α36 was attenuated after HMGA2 knockdown.ConclusionsHigh expression of ER-α36 was correlated with a poor prognosis in cervical cancer by regulating HMGA2. ER-α36 could be a prognostic biomarker and a target for cervical cancer treatment.
| S-EPMC8317436 | biostudies-literature
Project description:Treatment with either estradiol or an estrogen receptor (ER)alpha ligand has been shown to be both antiinflammatory and neuroprotective in a variety of neurological disease models, but whether neuroprotective effects could be observed in the absence of an antiinflammatory effect has remained unknown. Here, we have contrasted effects of treatment with an ERalpha vs. an ERbeta ligand in experimental autoimmune encephalomyelitis, the multiple sclerosis model with a known pathogenic role for both inflammation and neurodegeneration. Clinically, ERalpha ligand treatment abrogated disease at the onset and throughout the disease course. In contrast, ERbeta ligand treatment had no effect at disease onset but promoted recovery during the chronic phase of the disease. ERalpha ligand treatment was antiinflammatory in the systemic immune system, whereas ERbeta ligand treatment was not. Also, ERalpha ligand treatment reduced CNS inflammation, whereas ERbeta ligand treatment did not. Interestingly, treatment with either the ERalpha or the ERbeta ligand was neuroprotective, as evidenced by reduced demyelination and preservation of axon numbers in white matter, as well as decreased neuronal abnormalities in gray matter. Thus, by using the ERbeta selective ligand, we have dissociated the antiinflammatory effect from the neuroprotective effect of estrogen treatment and have shown that neuroprotective effects of estrogen treatment do not necessarily depend on antiinflammatory properties. Together, these findings suggest that ERbeta ligand treatment should be explored as a potential neuroprotective strategy in multiple sclerosis and other neurodegenerative diseases, particularly because estrogen-related toxicities such as breast and uterine cancer are mediated through ERalpha.
| S-EPMC1976208 | biostudies-literature
Project description:56 Estrogen Receptor Positive Breast cancer tissues coming from patients treated with tamoxifen upon recurrence (41 Good outcome vs 15 Poor outcome) have been microdissected to enrich for breast cancer tumor cells. Enriched tissue has been lysed and proteins digested and analyzed in an LTQ-Orbitrap coupled online with a Dionex nLC system. Thermo output .RAW files were analyzed through MaxQuant (version 1.4.1.2) using the human proteome FASTA (version 2012-09, human canonical proteome) as search library. LFQ parameters in MaxQuant have been enabled (Fast LFQ) and other settings have been kept as default.
2015-08-21 | PXD000485 | Pride
Project description:56 estrogen receptor positive breast cancer tissues from patients treated with tamoxifen upon recurrence (32 Good outcome vs 24 Poor outcome) have been microdissected to obtain a pure population of epithelial tumor cells. Breast tumor enriched tissues have been sonicated and proteins have been in-solution digested and analyzed via a LTQ-Orbitrap coupled online with a nano-LC system. Thermo output .RAW files were analyzed through MaxQuant (version 1.4.1.2) using the human proteome FASTA (version 2012-09, human canonical proteome) as search library.
2015-08-21 | PXD000484 | Pride
Project description:Breast cancer (BC) remains the most common cancer among women worldwide, and estrogen receptor-α expression is a critical diagnostic factor for BC. Estrogen receptor (ER-α36) is a dominant-negative effector of ER-α66-mediated estrogen-responsive gene pathways. ER-α36 is a novel target that mediates the non-genomic estrogen signaling pathway. However, the crystallized structure of ER-α36 remains unavailable for molecular studies. ER-positive and triple-negative BC tumors aggressively resist the FDA-approved drugs; therefore, highly potent structure-based inhibitors with preeminent benefits over toxicity will preferably replace the current BC treatment. Broussoflanol B (BFB), a B. papyrifera bark compound, exhibits potent growth inhibitory activity in ER-negative BC cells by inducing cell cycle arrest. For the first time, we unravel the comparative dynamic events of the enzymes' structures and the binding mechanisms of BFB when bound to the ER-α36 and ER-α66 ligand-binding domain using an all-atom molecular dynamics simulations approach and MM/PBSA-binding-free energy calculations. The dynamic findings have revealed that ER-α36 and ER-α66 LBD undergo timescale "coiling", opening and closing conformations favoring the high-affinity BFB-bound ER-α36 (ΔG = -52.57 kcal/mol) compared to the BFB-bound ER-α66 (ΔG = -42.41 kcal/mol). Moreover, the unbound (1.260 Å) and bound ER-α36 (1.182 Å) exhibit the highest flexibilities and atomistic motions relative to the ER-α66 systems. The RMSF (Å) of the unbound ER-α36 and ER-α66 exhibit lesser stabilities than the BFB-bound systems, resulting in higher structural flexibilities and atomistic motions than the bound variants. These findings present a model that describes the mechanisms by which the BFB compound induces downregulation-accompanied cell cycle arrest at the Gap0 and Gap1 phases.
| S-EPMC10741999 | biostudies-literature
Project description:BackgroundStroke is a sexually dimorphic disease and a leading cause of death and disability. Estrogen replacement therapy (ERT) confers beneficial neuroprotective effects if administered within a widely accepted time window called the "critical period." However, very few studies have explored the idea of modulating the critical period to enable long-term post-menopausal women to regain more benefits from estrogen therapy. Here, motivated by previous findings that electroacupuncture could both alter estrogen metabolism and induce significant tolerance against stroke, it was explored whether EA could restore estrogen's neuroprotection against cerebral ischemia in long-term ovariectomized (OVX) rats.MethodsWe implemented 1 week(w)-EA pretreatment on OVX-10w or OVX-20w rats, and tested the expression of estrogen receptors, and detected the ERT's neuroprotection against stroke induced by middle cerebral artery occlusion (MCAO).ResultsWe found that the expression levels of phospho-ERα-S118 and estrogen receptor β (ERβ) in the striatum of OVX-10w rats were significantly decreased and ERT's neuroprotection was abolished in the OVX-10w rats. However, EA-1w pretreatment could significantly recover the expression levels of phospho-ERα-S118 and ERβ, and also restored the neuroprotective effects of ERT in OVX-10w rats. However, EA-1w pretreatment could not restore the expression of estrogen receptors and ERT's neuroprotection in OVX-20w rats.ConclusionTaken together, our study indicates that EA may be an easy intervention that can restore the efficacy of estrogen therapy during the "critical period," which has the potential to improve the stroke outcomes of an enormous number of long-term post-menopausal women. However, the time-sensitive influences for how EA and estrogen metabolism interact with each other should be considered.
| S-EPMC8553307 | biostudies-literature
Project description:Estrogen receptor ? (ER?) is a major transducer of estrogen-mediated physiological signals. ER? is a member of the nuclear receptor superfamily, which encompasses ligand-dependent transcription factors. The C terminus of nuclear receptors, termed the F domain, is the least homologous region among the members of this family. The ER? F domain possesses 45 amino acids; however, its function remains unclear. We noticed that the homology of the F domains between mouse and human ER?s is remarkably lower (75.6% similarity) than that between the entire proteins (94.7% similarity). To assess the functionality of the ER? F domains, here we generated chimeric ER? expression constructs with mouse-human-exchanged F domains. Using cell-based in vitro assays, we analyzed the transcriptional coactivator interaction and ligand-binding domain dimerization activities of these mouse-human F domain-swapped ER?s. We found that the transcriptional activity of the mouse WT ER? is more potent than that of the human WT ER? in the human hepatoma cell line HepG2. 4-Hydroxytamoxifen (4OHT)-mediated transcriptional activity of mouse-human F domain-swapped ER?s was the inverse of the WT ER? activities but not estradiol-mediated transcriptional activities. Further experiments with constructs containing deletion or point mutations of a predicted ?-strand region within the F domain suggested that this region governs the species-specific 4OHT-mediated transcriptional activity of ER?. We conclude that the ER? F domain has a species-specific function in 4OHT-mediated receptor transactivation and that mouse-human F domain-swapped ER? mutants enable key insights into ER? F domain structure and function.
| S-EPMC5986198 | biostudies-literature