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Background: The treatment landscape for HR(+)HER2(−) metastatic breast cancer (MBC) is evolving for patients with ESR1 mutations (mut) and PI3K/AKT pathway genomic alterations (GA). We sought to inform clinical utility for comprehensive genomic profiling (CGP) using tissue (TBx) and liquid biopsies (LBx) in HR(+)HER2(−) MBC. Methods: Records from a de-identified breast cancer clinicogenomic database for patients who underwent TBx/LBx testing at Foundation Medicine during routine clinical care at ~ 280 US cancer clinics between 01/2011 and 09/2023 were assessed. GA prevalence [ESR1mut, PIK3CAmut, AKT1mut, PTENmut, and PTEN homozygous copy loss (PTENloss)] were calculated in TBx and LBx [stratified by ctDNA tumor fraction (TF)] during the first three lines of therapy. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared between groups by Cox models adjusted for prognostic factors. Results: ~ 60% of cases harbored 1 + GA in 1st-line TBx (1266/2154) or LBx TF ≥ 1% (80/126) and 26.5% (43/162) in LBx TF < 1%. ESR1mut was found in 8.1% TBx, 17.5% LBx TF ≥ 1%, and 4.9% LBx TF < 1% in 1st line, increasing to 59% in 3rd line (LBx TF ≥ 1%). PTENloss was detected at higher rates in TBx (4.3%) than LBx (1% in TF ≥ 1%). Patients receiving 1st-line aromatase inhibitor + CDK4/6 inhibitor (n = 573) with ESR1mut had less favorable rwPFS and rwOS versus ESR1 wild-type; no differences were observed for fulvestrant + CDK4/6 inhibitor (n = 348). Conclusion: Our study suggests obtaining TBx for CGP at time of de novo/recurrent diagnosis, followed by LBx for detecting acquired GA in 2nd + lines. Reflex TBx should be considered when ctDNA TF < 1%. [ABSTRACT FROM AUTHOR]

Background: There have been some studies on the occurrence of ESR1 and 2 polymorphisms and AIS, but some data extraction is wrong, and there are no studies on the progress of AIS. Methods: Computer searches were conducted on PubMed, EMBASE, ScienceDirect and Scopus from the establishment of the database to April 2024. Cross-sectional and case-control studies on estrogen receptor ESR1, two single nucleotide polymorphisms, and the occurrence and development of AIS were collected, and statistical analysis was performed using the Revman 5.3 software. Results: In the comparison of the association between single nucleotide polymorphisms of estrogen receptors ESR1 and 2 and the occurrence and development of AIS, eight studies were included, including 2706 cases and 1736 controls.The results showed that the AA genotype [OR = 0.50,95%Cl(0.34,0.72),P = 0.0003] at the XbaI locus of ESR1,CC genotype [OR = 1.67,95%Cl(1.16,2.42), P = 0.006], C allele [OR = 1.28,95%Cl(1.03,1.59),P = 0.03], and T allele [OR = 0.78,95%] Cl(0.63,0.97),P = 0.03] at the PvuII locus of ESR1 and TT genotype [OR = 0.50,95%Cl(0.26,0.93),P = 0.03] at the AlwNI locus of ESR2 showed statistically significant differences between the progressive and stable AIS patients. Conclusion: Single nucleotide polymorphisms of ESR1 and ESR2 were not related to the occurrence of AIS; however, some of them were related to the progression of AIS. [ABSTRACT FROM AUTHOR]

The objective of the present study was to find Single Nucleotide Polymorphisms (SNPs) in ESR1 and ESR2 genes and examine their association with egg production in chickens up to 64 weeks of age (EN64). Blood samples were taken from 48 Anand Synthetic White Leghorn (ASWLH) and 48 Anand Bantamised White Leghorn (ABWLH) chickens. Amplicon sequencing was carried out using the IlluminaMiseq platform, and a custom panel was developed to cover the exon regions of these genes. Total 91 SNPs, 59 previously reported and 32 novel SNPs were identified from 96 samples. In conclusion, the genetic variants g.52944897 T>C and rs3181386 inside the ESR2 gene exhibit potential as selection markers linked to EN64 in chickens. [ABSTRACT FROM AUTHOR]

Background/Aim: The aim of this study was to analyze rs2234693 and rs9340799 polymorphisms of the ESR1 gene in the context of breast cancer risk in Polish patients. Materials and Methods: The study involved a group of 117 patients with breast cancer and 106 controls. The analyses were carried out using the polymerase chain reaction – restriction fragments length polymorphism technique. Results: The presence of the CC genotype in rs2234693 more than doubled the risk of breast cancer (p=0.04), whereas the presence of the TT genotype in rs2234693 significantly reduced the risk of developing this type of cancer (p=0.0002). The presence of the GG genotype in rs9340799 more than doubled the risk of breast cancer (p=0.04), which was confirmed by the analysis of the recessive model (p=0.04). Conclusion: The polymorphisms rs2234693 and rs9340799 of the ESR1 gene may be associated with the risk of breast cancer among Polish women. [ABSTRACT FROM AUTHOR]

In this focused genetic case–control study, we analyzed two functional single-nucleotide variants (SNVs) associated with breast cancer risk (rs2046210, rs9383590) and one risk SNV for an implantation defect and infertility (rs9340799) for their association with endometriosis susceptibility, progression and ESR1 gene regulation in endometriosis patients. The rs2046210, rs9383590 and rs9340799 SNVs were genotyped in 153 endometriosis patients and 87 control subjects with Caucasian ancestry. We analyzed the association of all SNVs with endometriosis susceptibility in all patients and in subgroups and assessed the concordance between the SNVs. Quantitative reverse transcription PCR was used to determine ESR1 gene expression in the eutopic endometrial tissue of the controls and endometriosis patients. The heterozygous rs2046210 GA genotype was associated with significantly increased endometriosis risk, particularly in younger, leaner and infertile women and with an increased ESR1 gene expression in the eutopic endometrium of these patients, compared to controls. The minor AA genotype of rs2046210 was identified as a potential risk factor for endometriosis progression in women with mild endometriosis. The results from this analysis indicate that rs2046210 may be a functional genetic variant associated with endometriosis development and progression. [ABSTRACT FROM AUTHOR]

Abstract Background There have been some studies on the occurrence of ESR1 and 2 polymorphisms and AIS, but some data extraction is wrong, and there are no studies on the progress of AIS. Methods Computer searches were conducted on PubMed, EMBASE, ScienceDirect and Scopus from the establishment of the database to April 2024. Cross-sectional and case-control studies on estrogen receptor ESR1, two single nucleotide polymorphisms, and the occurrence and development of AIS were collected, and statistical analysis was performed using the Revman 5.3 software. Results In the comparison of the association between single nucleotide polymorphisms of estrogen receptors ESR1 and 2 and the occurrence and development of AIS, eight studies were included, including 2706 cases and 1736 controls.The results showed that the AA genotype [OR = 0.50,95%Cl(0.34,0.72),P = 0.0003] at the XbaI locus of ESR1,CC genotype [OR = 1.67,95%Cl(1.16,2.42), P = 0.006], C allele [OR = 1.28,95%Cl(1.03,1.59),P = 0.03], and T allele [OR = 0.78,95%] Cl(0.63,0.97),P = 0.03] at the PvuII locus of ESR1 and TT genotype [OR = 0.50,95%Cl(0.26,0.93),P = 0.03] at the AlwNI locus of ESR2 showed statistically significant differences between the progressive and stable AIS patients. Conclusion Single nucleotide polymorphisms of ESR1 and ESR2 were not related to the occurrence of AIS; however, some of them were related to the progression of AIS.

Abstract Background Estrogen receptors express in nearly 70% of breast cancers (ER-positive). Estrogen receptor alpha plays a fundamental role as a significant factor in breast cancer progression for the early selection of therapeutic approaches. Accordingly, there has been a surge of attention to non-invasive techniques, including circulating Cell-free DNA (ccfDNA) or Cell-Free DNA (cfDNA), to detect and track ESR1 genotype. Therefore, this study aimed to examine the diagnosis accuracy of ESR1 mutation detection by cell-free DNA in breast cancer patientsthrough a systematic review and comprehensive meta-analysis. Methods PubMed, Embase, and Web of Science databases were searched up to 6 April 2022. Diagnostic studies on ESR1 measurement by cfDNA, which was confirmed using the tumour tissue biopsy, have been included in the study. The sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were considered to analyse the data. Results Out of 649 papers, 13 papers with 15 cohorts, including 389 participants, entered the meta-analyses. The comprehensive meta-analysis indicated a high sensitivity (75.52, 95% CI 60.19–90.85), specificity (88.20, 95% CI 80.99–95.40), and high accuracy of 88.96 (95% CI 83.23–94.69) for plasma ESR1. We also found a moderate PPV of 56.94 (95% CI 41.70–72.18) but a high NPV of 88.53 (95% CI 82.61–94.44). We also found an NLR of 0.443 (95% CI 0.09–0.79) and PLR of 1.60 (95% CI 1.20–1.99). Conclusion This systematic review and comprehensive meta-analysis reveal that plasma cfDNA testing exhibits high sensitivity and specificity in detecting ESR1 mutations in breast cancer patients. This suggests that the test could be a valuable diagnostic tool. It may serve as a dependable and non-invasive technique for identifying ESR1 mutations in breast cancer patients. However, more extensive research is needed to confirm its prognostic value.

Background: Estrogen receptors express in nearly 70% of breast cancers (ER-positive). Estrogen receptor alpha plays a fundamental role as a significant factor in breast cancer progression for the early selection of therapeutic approaches. Accordingly, there has been a surge of attention to non-invasive techniques, including circulating Cell-free DNA (ccfDNA) or Cell-Free DNA (cfDNA), to detect and track ESR1 genotype. Therefore, this study aimed to examine the diagnosis accuracy of ESR1 mutation detection by cell-free DNA in breast cancer patientsthrough a systematic review and comprehensive meta-analysis. Methods: PubMed, Embase, and Web of Science databases were searched up to 6 April 2022. Diagnostic studies on ESR1 measurement by cfDNA, which was confirmed using the tumour tissue biopsy, have been included in the study. The sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were considered to analyse the data. Results: Out of 649 papers, 13 papers with 15 cohorts, including 389 participants, entered the meta-analyses. The comprehensive meta-analysis indicated a high sensitivity (75.52, 95% CI 60.19–90.85), specificity (88.20, 95% CI 80.99–95.40), and high accuracy of 88.96 (95% CI 83.23–94.69) for plasma ESR1. We also found a moderate PPV of 56.94 (95% CI 41.70–72.18) but a high NPV of 88.53 (95% CI 82.61–94.44). We also found an NLR of 0.443 (95% CI 0.09–0.79) and PLR of 1.60 (95% CI 1.20–1.99). Conclusion: This systematic review and comprehensive meta-analysis reveal that plasma cfDNA testing exhibits high sensitivity and specificity in detecting ESR1 mutations in breast cancer patients. This suggests that the test could be a valuable diagnostic tool. It may serve as a dependable and non-invasive technique for identifying ESR1 mutations in breast cancer patients. However, more extensive research is needed to confirm its prognostic value. [ABSTRACT FROM AUTHOR]

Background: Traditional Chinese medicine is promising for managing challenging and complex disorders, including cancer, and in particular, saffron is applied in treating various cancer types. However, its potential therapeutic efficacy and active components in managing squamous cell carcinoma of the head and neck (HNSCC) remain unclear yet. Methods: Using network pharmacology approaches, active ingredients of saffron, their target genes, and HNSCC-related genes were identified. Enrichment analyses were conducted for determining molecular functions and pathways enriched by genes that overlapped between the saffron target gene set and the HNSCC gene set. Among the four known active ingredients of saffron, crocetin was found to have the strongest inhibitory impact on HNSCC, based on the findings of cell viability and migration assays. Therefore, the potential target genes of crocetin in HNSCC cells were examined using molecular docking experiments and were confirmed by qPCR. Results: Four active ingredients of saffron and 184 of their target genes were identified. Further, a total of 34 overlapping saffron-/HNSCC-associated targets related to the four active ingredients were screened, and crocetin was chosen for further investigation because it had the strongest inhibitory effect on HNSCC cells. Molecular docking experiments indicated that ESR1 and CCND1 were the target genes of crocetin. These results were confirmed through qPCR analysis, in which crocetin was found to lower the expression of the ESR1 and CCND1 genes in AMC-HN-8 and FaDu cells. Conclusion: According to our results, crocetin is a primary active anti-cancer component of saffron that may have potential in the development of novel HNSCC-treating medications. However, more thorough molecular research is necessary for confirming these results and elucidating the anti-cancer mechanism underlying saffron. [ABSTRACT FROM AUTHOR]

The Fucaceae family of marine brown algae includes Ascophyllum nodosum. Fucosterol (FSL) is a unique bioactive component that was identified through GC-MS analysis of the hydroalcoholic extract of A. nodosum. Fucosterol's mechanism of action towards hepatocellular cancer was clarified using network pharmacology and docking study techniques. The probable target gene of FSL has been predicted using the TargetNet and SwissTargetPred databases. GeneCards and the DisGNet database were used to check the targeted genes of FSL. By using the web programme Venny 2.1, the overlaps of FSL and HCC disease demonstrated that 18 genes (1.3%) were obtained as targeted genes Via the STRING database, a protein–protein interaction (PPI) network with 18 common target genes was constructed. With the aid of CytoNCA, hub genes were screened using the Cytoscape software, and the targets' hub genes were exported into the ShinyGo online tool for study of KEGG and gene ontology enrichment. Using the software AutoDock, a hub gene molecular docking study was performed. Ten genes, including AR, CYP19A1, ESR1, ESR2, TNF, PPARA, PPARG, HMGCR, SRC, and IGF1R, were obtained. The 10 targeted hubs docked with FSL successfully. The active components FSL of ASD, the FSL, are engaged in fatty liver disease, cancer pathways, and other signalling pathways, which could prove beneficial for the management of HCC. [ABSTRACT FROM AUTHOR]

Annual breast cancer (BCa) deaths have declined since its apex in 1989 concomitant with widespread adoption of hormone therapies that target estrogen receptor alpha (ERα), the prominent nuclear receptor expressed in ∼80% of BCa. However, up to ∼50% of patients who are ER+ with high-risk disease experience post endocrine therapy relapse and metastasis to distant organs. The vast majority of BCa mortality occurs in this setting, highlighting the inadequacy of current therapies. Genomic abnormalities to ESR1 , the gene encoding ERα, emerge under prolonged selective pressure to enable endocrine therapy resistance. These genetic lesions include focal gene amplifications, hotspot missense mutations in the ligand binding domain, truncations, fusions, and complex interactions with other nuclear receptors. Tumor cells utilize aberrant ERα activity to proliferate, spread, and evade therapy in BCa as well as other cancers. Cutting edge studies on ERα structural and transcriptional relationships are being harnessed to produce new therapies that have shown benefits in patients with ESR1 hotspot mutations. In this review we discuss the history of ERα, current research unlocking unknown aspects of ERα signaling including the structural basis for receptor antagonism, and future directions of ESR1 investigation. In addition, we discuss the development of endocrine therapies from their inception to present day and survey new avenues of drug development to improve pharmaceutical profiles, targeting, and efficacy. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent malignancy in women, and is characterized by its heterogeneity; exhibiting various subgroups identifiable through molecular biomarkers that also serve as predictive indicators. More than two thirds of breast tumors are classified as luminal with positive hormone receptors (HR), indicating that cancer cells proliferation is promoted by hormones. Endocrine therapies play a vital role in the effective treatment of breast cancer by manipulating the signaling of estrogen receptors (ER), leading to a reduction in cell proliferation and growth rate. Selective estrogen receptor modulators (SERMs), such as tamoxifen and toremifene, function by blocking estrogen's effects. Aromatase inhibitors (AI), including anastrozole, letrozole and exemestane, suppress estrogen production. On the other hand, selective estrogen receptor degraders (SERDs), like fulvestrant, act by blocking and damaging estrogen receptors. Tamoxifen and AI are widely used both in early- and advancedstage disease, while fulvestrant is used as a single agent or in combination with other agents like the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib, ribociclib) or alpelisib for advanced-stage disease. Currently, SERDs are recognized as an effective therapeutic approach for the treatment of ER-positive breast cancer, showing proficiency in reducing and blocking ER signaling. This review aims to outline the ongoing development of novel oral SERDs from a practical therapeutic perspective, enhancing our understanding of the mechanisms of action underlying these compounds. [ABSTRACT FROM AUTHOR]

Introduction: Estrogens are crucial regulators of ovarian function, mediating their signaling through binding to estrogen receptors. The disruption of the estrogen receptor 1 (Esr1) provokes infertility associated with a hemorrhagic, cystic phenotype similar to that seen in diseased or aged ovaries. Our previous study indicated the possibility of altered iron metabolism in Esr1-deficient ovaries showing massive expression of lipocalin 2, a regulator of iron homeostasis. Methods: Therefore, we examined the consequences of depleting Esr1 in mouse ovaries, focusing on iron metabolism. For that reason, we compared ovaries of adult Esr1-deficient animals and age-matched wild type littermates. Results and discussion: We found increased iron accumulation in Esr1-deficient animals by using laser ablation inductively coupled plasma mass spectrometry. Western blot analysis and RT-qPCR confirmed that iron overload alters iron transport, storage and regulation. In addition, trivalent iron deposits in form of hemosiderin were detected in Esr1-deficient ovarian stroma. The depletion of Esr1 was further associated with an aberrant immune cell landscape characterized by the appearance of macrophage-derived multinucleated giant cells (MNGCs) and increased quantities of macrophages, particularly M2-like macrophages. Similar to reproductively aged animals, MNGCs in Esr1-deficient ovaries were characterized by iron accumulation and strong autofluorescence. Finally, deletion of Esr1 led to a significant increase in ovarian mast cells, involved in iron-mediated foam cell formation. Given that these findings are characteristics of ovarian aging, our data suggest that Esr1 deficiency triggers mechanisms similar to those associated with aging. [ABSTRACT FROM AUTHOR]

Breast cancer (BRCA) is the most common malignancies worldwide with increasing rate. Dolichol phosphate mannose synthase (DPMS) is a critical mannosyltransferase involved in the posttranslational modification of proteins. At present, there is limited knowledge regarding the function of DPMS in breast cancer. In this study, silica analysis in multiple datasets found that dolichyl‐phosphate mannosyltransferase subunit 2 (DPM2) is an unfavorable prognostic marker, suggesting its oncogenic role. Cell counting kit‐8 and apoptosis assays show that DPM2‐silenced cancer cells exhibit decreased growth potential and enhanced cell death rate. Further, transwell and wound healing assays show reduced invasion and migration capabilities in DPM2 knockdown groups, xenograft nude mice model demonstrated smaller tumor volume in DPM2 silenced BC cells. Then, the underlying downstream mechanism of DPM2 in BC was predicted and analyzed, highlighting classical tumorigenic pathways like JAK/STAT signaling pathway and oxidative phosphorylation activated in the cancer group. Finally, ChIP‐seq analysis, expression correlation analysis, inhibitor treatment, and dual luciferase assays show that DPM2 is transcriptionally activated by estrogen receptor1 (ESR1). The results show that high expression of DPM2 mRNA is significantly correlated with shorter overall survival (OS) and disease‐free survival (DFS) in breast cancer patients, and in vitro knockdown of DPM2 can significantly inhibit the malignant phenotypes of cells, including proliferation, invasion, migration, and apoptosis. These results suggest that DPM2 may play an important role in breast cancer. Altogether, we first uncovered the tumorigenic and prognostic role of DPM2 in breast cancer, cellular assays, and bioinformatics analysis highlighted DPM2 as oncogene via inhibited cancer‐related signaling pathways in breast cancer. Besides, DPM2 is transcriptionally activated by ESR1, the signaling axis of ESR1/DPM2 provides a new strategy for BC‐targeted therapy. [ABSTRACT FROM AUTHOR]

The current study was conducted in Dhi Qar Governorate on young women suffering from Breast Cancer (BC), where their ages ranged exclusively between (20-40) years. It was the first study in the governorate to address young ages only, to highlight the spread of this serious disease in young groups and to know Its relationship with genetic causes and genotypes. The aim of the current study is to investigate genetic mutations of the estrogen receptor gene (ESR1 rs1062577) and its relationship to breast cancer risk in young women. This study included (100) randomly collected samples, divided into two groups: the first group consisted of ( 80 ) of blood samples from patients undergoing surgical intervention, breast biopsy, and follow-up at Al-Haboubi Hospital/Oncology Unit/Dhi -Qar province, which is a specialized department for treating cancer patients. The second group consisted of (20) samples from healthy young women. The study was conducted from February 2023 to July 2023. The results of the Tetra ARMS-PCR analysis for the estrogen receptor gene ESR1 rs1062577 revealed the presence of two alleles,A and T and three genotypic patterns, AA, AT, and TT, in both the breast cancer patients and the control group. The allele A was recorded at a percentage of 58.75% in the patient sample compared to the allele T,,which was recorded at a percentage of 41.25% In contrast, the allele A was present at a percentage of 100% in the control sample, while the allele t did not appear and had a percentage of 0%. No significant differences were found at a significance level of p 0.05 < . Increased the incidence of breast cancer among the young age group in Iraq and in our province ( Dhi-qar) so at limited time of our study we can collect good number of patient diagnosed with invasive breast cancer in age between (20-40) year,These results can predict and give idea about prognostic staging and fate of this dangerous cancer especially in young age group who may be lived for long time after diagnosis of cancer, Study the type of genetic mutation for estrogen receptors as important cause for incidence of breast cancer cases. [ABSTRACT FROM AUTHOR]

Estrogen actions are mediated by both nuclear (n) and membrane (m) localized estrogen receptor 1 (ESR1). Male Esr1 knockout (Esr1 KO) mice lacking functional Esr1 are infertile, with reproductive tract abnormalities. Male mice expressing nESR1 but lacking mESR1 (nuclear-only estrogen receptor 1 mice) are progressively infertile due to testicular, rete testis, and efferent ductule abnormalities similar to Esr1 KO males, indicating a role for mESR1 in male reproduction. The H2NES mouse expresses only mESR1 but lacks nESR1. The goal of this study was to identify the functions of mESR1 alone in mice where nESR1 was absent. Breeding trials showed that H2NES males are fertile, with decreased litter numbers but normal pup numbers/litter. In contrast to Esr1 KO mice, H2NES testicular, and epididymal weights were not reduced, and seminiferous tubule abnormalities were less pronounced. However, Esr1 KO and H2NES males both had decreased sperm motility and a high incidence of abnormal sperm morphology. Seminiferous tubule and rete testis dilation and decreased efferent ductule epithelial height characteristic of Esr1 KO males were reduced in H2NES. Consistent with this, expression of genes involved in fluid transport and ion movement that were reduced in Esr1 KO (Aqp1 , Car2 , Car14 , Cftr) were partially or fully restored to wild-type levels in H2NES. In summary, in contrast to Esr1 KO males, H2NES males are fertile and have reduced phenotypic and functional abnormalities in the testis and efferent ductules. Thus, mESR1 alone, in the absence of nESR1, can partially regulate male reproductive tract structure and function, emphasizing its importance for overall estrogen action. [ABSTRACT FROM AUTHOR]

Background: An accurate status determination of breast cancer biomarkers (ER, PR, HER2, Ki67) is crucial for guiding patient management. The "gold standard" for assessing these biomarkers in FFPE tissue is IHC, which faces challenges in standardization and exhibits substantial variability. In this study, we compare the concordance of a new commercial RT-qPCR kit with IHC in determining BC biomarker status. Methods: The performance was evaluated using 634 FFPE specimens, which underwent histological analysis in accordance with standard of care methods. HER2 2+ tumors were referred to ISH testing. An immunoreactive score of ≥2/12 was considered positive for ER/PR and 20% staining was used as a cut-off for Ki67 high/low score. RT-qPCR and results calling were performed according to the manufacturer's instructions. Results: High concordance with IHC was seen for all markers (93.2% for ER, 87.1% for PR, 93.9% for HER2, 77.9% for Ki67 and 80.1% for proliferative signature (assessed against Ki67 IHC)). Conclusions: By assessing the concordance with the results obtained through IHC, we sought to demonstrate the reliability and utility of the kit for precise BC subtyping. Our findings suggest that the kit provides a highly precise and accurate quantitative assessment of BC biomarkers. [ABSTRACT FROM AUTHOR]

Background: Despite the increasing availability of therapeutic drugs for autoimmune diseases, many patients still struggle to achieve their treatment goals. Our aim was to identify whether drugs originally used to treat bone density could be applied to the treatment of autoimmune diseases through Mendelian randomization (MR). Methods: Using summary statistics from genome-wide association studies, we used a two-sample MR design to estimate the correlation between autoimmune diseases and BMD-related drug targets. Data from the DrugBank and ChEMBL databases were used to identify the drug targets of anti-osteoporosis medications. The Wald ratio test or inverse-variance weighting method was used to assess the impact of genetic variation in drug target(s) on autoimmune disease therapy. Results: Through our analysis, we discovered a negative correlation between genetic variability in a specific gene (ESR1) in raloxifene/colecalciferol and various autoimmune disorders such as ankylosing spondylitis, endometriosis, IgA nephropathy, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, and type 1 diabetes. Conclusion: These results indicate a possible link between genetic differences in the drug targeting ESR1 and susceptibility to autoimmune disorders. Hence, our study offers significant support for the possible use of drugs targeting ESR1 for the management of autoimmune disorders. MR and drug repurposing are utilized to investigate the relationship between autoimmune diseases and bone mineral density, with a focus on ESR1.

Background: ESR1 is expressed by 60–70% of breast tumours. it's a good prognosis factor and the target of hormone therapy. Optimization of ESR1 reactivation therapy is currently ongoing. Here we probe if the transcription factor CTCF plays a role in the differential expression of ESR1 in the breast cancer cell lines MCF-7 (ESR1+) and MDA-MB-231 (ESR1-). Methods and results: Knockdown of CTCF in MCF-7 resulted in decreased ESR1 gene expression. CTCF binds to the promoter of ESR1 in MCF-7 but not in MDA-MB-231 cells. CTCF ESR1 binding sites are unmethylated in MCF7 but methylated in MDA-MB-231 cells. Conclusion: ESR1 expression in MCF7 cells is dependent on CTCF expression. CTCF can bind to specific regions of the promotor of ESR1 gene in MCF-7 cells but not in MDA-MB-231 cells, this correlates with the methylation status of these regions and could be involved in the transcriptional regulation of ESR1. [ABSTRACT FROM AUTHOR]

Purpose Breast cancer is one of the most common causes of cancer-related death in females. Numerous drug-targetable biomarkers and predictive biomarkers have been developed. Some researchers have expressed doubts about the need for next-generation sequencing (NGS) studies in daily practice. This study analyzed the results of NGS studies on breast cancer at a single institute and evaluated the real-world applications of NGS data to precision medicine for breast cancer. Materials and Methods We retrospectively collected the results of NGS studies and analyzed the histopathologic features and genetic profiles of patients treated for breast cancer from 2010 to 2021. Seventy cases had data from CancerSCAN, a customized panel of 375 cancer-associated genes, and 110 cases had data from TruSight Oncology 500. Results The most frequently detected single nucleotide variant was the TP53 mutation (123/180, 68.3%), followed by PIK3CA mutations (51/180, 28.3%). Estrogen receptor 1 (ESR1) mutation was detected in 11 patients (6.1%), of whom 10 had hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, and two had no history of prior endocrine therapy. Based on their NGS study results, 13 patients (7.2%) received target therapy. Among them, four patients had a BRCA1 or BRCA2 germline mutation, and nine patients had a PIK3CA mutation. Conclusion NGS can provide information about predictive biomarkers and drug-targetable biomarkers that can enable treatment and participation in clinical trials based on precision medicine. Further studies should be conducted to excavate novel drug-targetable biomarkers and develop additional target therapies. [ABSTRACT FROM AUTHOR]

Purpose: Hypercalcemic primary hyperparathyroidism (PHPT) is a common endocrine disorder that has been very well characterized. In contrast, many aspects of normocalcemic primary hyperparathyroidism (NPHPT) such as natural history, organ damage, and management are still matter of debate. In addition, both the pathophysiology and molecular basis of NPHPT are unclear. We investigated whether PHPT and NPHPT patient cohorts share the same pattern of genetic variation in genes known to be involved in calcium and/or bone metabolism. Research design and methods: Genotyping for 9 single nucleotide polymorphisms (SNPs) was performed by Real-Time PCR (TaqMan assays) on 27 NPHPT and 31 PHPT patients evaluated in a tertiary referral Center. The data of both groups were compared with 54 in house-controls and 503 subjects from the 1000 Genomes Project. All groups were compared for allele/haplotype frequencies, on a single locus, two loci and multi-locus basis. Results: The NPHPT group differed significantly at SNPs in OPG and ESR1. Also, the NPHPT cohort was peculiar for pairwise associations of genotypes and for the overrepresentation of unusual multilocus genotypes. Conclusions: Our NPHPT patient set harbored a definitely larger quota of genetic diversity than the other samples. Specific genotypes may help in defining subgroups of NPHPT patients which deserve ad hoc clinical and follow-up studies. [ABSTRACT FROM AUTHOR]

Passion fruit peel fermentation extract (PFPFE) increased gastrointestinal transport power and fecal moisture content, protected the structural integrity of colon tissue, and reduced inflammatory infiltration. PFPFE also increased secretion of the ET-1, GAS, MTL, and SP, and decreased secretion of the inhibitory SS and VIP. In addition, PFPFE alleviated perirectal redness and hemorrhage in hemorrhoid mice, and downregulated levels of the serum inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β). In this study, we also analyzed the main active components and core targets of PFPFE for alleviating constipation and hemorrhoids through network pharmacology, and predicted its mechanism of action. Finally, we carried out Western blot experiments to verify that PFPFE and its active component kae alleviates constipation and hemorrhoids in mice by downregulating ESR1 and PI3K/Akt pathways. These results provide a scientific basis for the development of PFPFE as a functional food for alleviating constipation and hemorrhoids.

IntroductionEstrogens are crucial regulators of ovarian function, mediating their signaling through binding to estrogen receptors. The disruption of the estrogen receptor 1 (Esr1) provokes infertility associated with a hemorrhagic, cystic phenotype similar to that seen in diseased or aged ovaries. Our previous study indicated the possibility of altered iron metabolism in Esr1-deficient ovaries showing massive expression of lipocalin 2, a regulator of iron homeostasis.MethodsTherefore, we examined the consequences of depleting Esr1 in mouse ovaries, focusing on iron metabolism. For that reason, we compared ovaries of adult Esr1-deficient animals and age-matched wild type littermates. Results and discussionWe found increased iron accumulation in Esr1-deficient animals by using laser ablation inductively coupled plasma mass spectrometry. Western blot analysis and RT-qPCR confirmed that iron overload alters iron transport, storage and regulation. In addition, trivalent iron deposits in form of hemosiderin were detected in Esr1-deficient ovarian stroma. The depletion of Esr1 was further associated with an aberrant immune cell landscape characterized by the appearance of macrophage-derived multinucleated giant cells (MNGCs) and increased quantities of macrophages, particularly M2-like macrophages. Similar to reproductively aged animals, MNGCs in Esr1-deficient ovaries were characterized by iron accumulation and strong autofluorescence. Finally, deletion of Esr1 led to a significant increase in ovarian mast cells, involved in iron-mediated foam cell formation. Given that these findings are characteristics of ovarian aging, our data suggest that Esr1 deficiency triggers mechanisms similar to those associated with aging.

In this focused genetic case–control study, we analyzed two functional single-nucleotide variants (SNVs) associated with breast cancer risk (rs2046210, rs9383590) and one risk SNV for an implantation defect and infertility (rs9340799) for their association with endometriosis susceptibility, progression and ESR1 gene regulation in endometriosis patients. The rs2046210, rs9383590 and rs9340799 SNVs were genotyped in 153 endometriosis patients and 87 control subjects with Caucasian ancestry. We analyzed the association of all SNVs with endometriosis susceptibility in all patients and in subgroups and assessed the concordance between the SNVs. Quantitative reverse transcription PCR was used to determine ESR1 gene expression in the eutopic endometrial tissue of the controls and endometriosis patients. The heterozygous rs2046210 GA genotype was associated with significantly increased endometriosis risk, particularly in younger, leaner and infertile women and with an increased ESR1 gene expression in the eutopic endometrium of these patients, compared to controls. The minor AA genotype of rs2046210 was identified as a potential risk factor for endometriosis progression in women with mild endometriosis. The results from this analysis indicate that rs2046210 may be a functional genetic variant associated with endometriosis development and progression.

Background: Molecular markers are involved in atopic dermatitis (AD) pathogenesis. The estrogen receptor (ESR)-1 gene, encoding ERα, is reported to express aberrantly in AD patients.Objective: To detect the biological functions of ESR1 in 2,4 dinitrochlorobenzene (DNCB)-treated mice.Methods: The DNCB-treated mice received a topical application of emulsion containing the 1,3-bis(4 hydroxyphenyl)-4-methyl-5-[4-(2-piperidinyl ethoxy) phenol]-1H-pyrazole dihydrochloride (MPP; an ESR1-selective antagonist) to dorsal skins and ears. Then the dermatitis scores, histopathological changes, and cytokine levels were evaluated.Results: MPP specifically downregulated ESR1 expression in DNCB-applied mice. Functionally, application of MPP abolished the DNCB-induced promotion in dermatitis score. Additionally, MPP administration protected against DNCB-induced dermatitis severity, suppressed mast cell infiltration and reduced production of immunoglobulin E (IgE) and thymus and activation-regulated chemokine (TARC). Moreover, MPP treatment inhibited DNCB- induced production of Th2 cytokines and infiltration of CD4+ T cells.Conclusion: ESR1 facilitates Th2-immune response and enhances Th2 cytokines in AD mice.

Context: We have previously reported that a specific “AGATC” haplotype in a >34 kb tight linkage disequilibrium (LD) block within ESR1 is strongly associated with cryptorchidism and hypospadias in Japanese boys. Objective: We aimed to determine the true susceptibility factor for cryptorchidism and hypospadias linked to the “AGATC” haplotype. Methods: We performed various molecular studies in hitherto unreported 230 Italian boys (80 with cryptorchidism and 150 with normal genitalia) and previously reported and newly recruited 415 Japanese boys (149 with cryptorchidism, 141 with hypospadias, and 125 with normal genitalia). We also performed ESR1 expression analyses using breast cancer–derived MCF-7 cells. Results: Haplotype analysis revealed the LD block and positive association of the “AGATC” haplotype with cryptorchidism in Italian boys. Whole genome sequencing identified an identical 2249-bp microdeletion (ΔESR1) generated by a microhomology-mediated replication error in both Japanese and Italian boys with the specific haplotype. ΔESR1 was found to be strongly associated with cryptorchidism and hypospadias by Cochran-Armitage trend test and was revealed to show nearly absolute LD with the “AGATC” haplotype. ESR1 expression was upregulated in MCF-7 cells with a homozygous deletion encompassing ΔESR1 and those with a homozygous deletion involving a CTCF-binding site within ΔESR1. Conclusion: The results reveal that ΔESR1, which has been registered as “DEL_6_75504” in gnomAD SVs v2.1, is the true susceptibility factor for cryptorchidism and hypospadias. It appears that ΔESR1 was produced in a single ancestral founder of modern humans and has been maintained within the genome of multiple ethnic groups by selection. [ABSTRACT FROM AUTHOR]

Several retrospective and prospective studies have shown that genomic alterations in Estrogen-receptor one (ESR1) can be characterized not only in tissue samples but also by sequencing circulating tumor DNA (ctDNA) in liquid biopsy. Therefore, liquid biopsy is a potential noninvasive surrogate for tissue biopsy. This meta-analysis was designed to compare the prevalence of ESR 1 mutation detected with liquid biopsy and tissue biopsy. A pooled meta-analysis of studies published between 1 January 2007 and 1 March 2021 was conducted regarding the methodologies used for ESR1 mutation analysis. Liquid biopsy is a valid, inexpensive, and attractive noninvasive alternative to tumor biopsies for the identification of ESR1 mutations. Liquid biopsy for ESR 1 analysis would facilitate regular testing, allowing monitoring of the sensitivity to ET and guiding treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Long-term environmental exposure to metals leads to epigenetic changes and may increase risks to human health. The relationship between the type and level of metal exposure and epigenetic changes in subjects exposed to high concentrations of metals in the environment is not yet clear. The aim of our study is to find the possible association of environmental long-term exposure to metals with DNA methylation changes of genes related to immune response and carcinogenesis. We investigated the association of plasma levels of 21 essential and non-essential metals detected by ICP-MS and the methylation level of 654 CpG sites located on NFKB1, CDKN2A, ESR1, APOA5, IGF2 and H19 genes assessed by targeted bisulfite sequencing in a cohort of 40 subjects living near metal mining area and 40 unexposed subjects. Linear regression was conducted to find differentially methylated positions with adjustment for gender, age, BMI class, smoking and metal concentration. Results: In the metal-exposed group, five CpGs in the NFKB1 promoter region were hypomethylated compared to unexposed group. Four differentially methylated positions (DMPs) were associated with multiple metals, two of them are located on NFKB1 gene, and one each on CDKN2A gene and ESR1 gene. Two DMPs located on NFKB1 (chr4:102500951, associated with Be) and IGF2 (chr11:2134198, associated with U) are associated with specific metal levels. The methylation status of the seven CpGs located on NFKB1 (3), ESR1 (2) and CDKN2A (2) positively correlated with plasma levels of seven metals (As, Sb, Zn, Ni, U, I and Mn). Conclusions: Our study revealed methylation changes in NFKB1, CDKN2A, IGF2 and ESR1 genes in individuals with long-term human exposure to metals. Further studies are needed to clarify the effect of environmental metal exposure on epigenetic mechanisms and pathways involved. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most prevalent kind of cancer worldwide and the main reason why people die from cancer. Represents 18% of all malignancies in women. and second most common type of cancer after lung cancer. Objective: In this study, ESR1, EGFR2 and human vitamin D3 were investigated in Iraqi women breast cancer patients. Patients and methods: In this study, serum concentrations of ESR1, EGFR2 and HUMAN VITAMIN D3 were determined using samples from 90 Iraqi women (60 patients and 30 healthy volunteers) Among them are healthy and patients, premenopausal and postmenopausal woman. Results: According to the findings of the current study, ESR1, EGFR2 and were both considerably elevated in breast cancer patients (P<0.05), and they also had a tight relationship, and human vitaminD3 was a decrease in patients with breast cancer on the probability level (P<0.05). Conclusions: This research discovered a link between high serum levels of ESR1, EGFR2, and its inverse relationship with vitamin D. [ABSTRACT FROM AUTHOR]

Abstract Background Uterine fibroids (UFs) are uterine smooth muscle neoplasms that affect women, especially during the reproductive stage. Both genetic and lifestyle factors affect the onset of the disease. We examined the association between the estrogen receptor 1 (ESR1) rs2234693 variant (whose genotypes are TT, TC, and CC) and UFs in Taiwanese premenopausal and postmenopausal women. Methods We linked individual-level data of 3588 participants from the Taiwan Biobank to the National Health Insurance Research Database at the Health and Welfare Data Science Center. The association of the ESR1 rs2234693 variant and other variables with UFs was determined by multiple logistic regression, and the results were presented as odds ratios and 95% confidence intervals (CIs). Results The 3588 participants comprised 622 cases and 2966 controls. In all the participants, the ESR1 rs2234693 TC and CC genotypes compared to the reference genotype (TT) were associated with a lower risk of UFs. However, the results were significant only for the CC genotype (OR; 95% CI = 0.70; 0.52–0.93). Noteworthy, the association of TC and CC with UFs was dose-dependent (p-trend = 0.012). Based on menopausal status, both TC and CC were significantly and dose-dependently associated with a lower risk of UFs in premenopausal women (OR; 95% CI = 0.76; 0.59–0.98 for TC and 0.64; 0.43–0.95 for CC: p-trend = 0.010). Conclusion The TC and CC genotypes of the ESR1 rs2234693 variant may reduce susceptibility to UFs, especially in premenopausal women.

Several retrospective and prospective studies have shown that genomic alterations in Estrogen-receptor one (ESR1) can be characterized not only in tissue samples but also by sequencing circulating tumor DNA (ctDNA) in liquid biopsy. Therefore, liquid biopsy is a potential noninvasive surrogate for tissue biopsy. This meta-analysis was designed to compare the prevalence of ESR 1 mutation detected with liquid biopsy and tissue biopsy. A pooled meta-analysis of studies published between 1 January 2007 and 1 March 2021 was conducted regarding the methodologies used for ESR1 mutation analysis. Liquid biopsy is a valid, inexpensive, and attractive noninvasive alternative to tumor biopsies for the identification of ESR1 mutations. Liquid biopsy for ESR 1 analysis would facilitate regular testing, allowing monitoring of the sensitivity to ET and guiding treatment strategies.

Simple Summary: Our study successfully cloned and obtained an 1866 bp segment of the full-length coding sequence (CDS) region of the estrogen receptor gene 1 (ESR1) in Sichuan white geese. We compared the involvement of ESR1 in lipid metabolism between pre-hierarchical granulosa cells and hierarchical granulosa cells in geese. Our findings indicate that ESR1 plays a more significant role in the lipid metabolism of hierarchical granulosa cells. When ESR1 is overexpressed in hierarchical granulosa cells, it leads to a reduction in lipid droplet deposition, cholesterol, and triglycerides, primarily regulated by APOB and PPARα, which control lipoprotein synthesis. Conversely, interfering with ESR1 in hierarchical granulosa cells results in increased lipid droplet deposition, cholesterol, and triglycerides. This increase is jointly mediated by ACCα, DGAT1, and SCD, which regulate fatty acid synthesis, as well as CPT1 and ATGL, which are involved in fatty acid degradation. (1) Background: The role of estrogen receptor gene 1 (ESR1) in female reproduction and lipid metabolism has been extensively investigated. However, its contribution to lipid metabolism during the development of poultry follicles remains unclear. (2) Methods: This study aimed to explore the function of ESR1 via overexpressing (ESR1ov) and interfering (ESR1si) with its expression in pre-hierarchical granulosa cells (phGCs) and hierarchical granulosa cells (poGCs). (3) Results: We successfully cloned and obtained an 1866 bp segment of the full-length CDS region of the Sichuan white goose ESR1 gene. In phGCs of the ESR1ov and ESR1si groups, there were no significant changes compared to the control group. However, in poGCs, the ESR1ov group exhibited decreased lipid deposition, triglycerides, and cholesterol compared to the control group, while the ESR1si group showed increased lipid deposition, triglycerides, and cholesterol. The expression of APOB and PPARα was significantly reduced in the ESR1ov group compared to the ESR1ov-NC group. Moreover, significant changes in the expression of ACCα, DGAT1, SCD, CPT1, and ATGL were observed between the ESR1si and ESR1si-NC group. (4) Conclusions: These findings shed light on the function and molecular mechanism of ESR1 in lipid metabolism in goose poGCs, providing a better understanding of the physiological process of goose follicular development. [ABSTRACT FROM AUTHOR]

Aim. To evaluate an impact of different S6K1 isoforms expression in MCF-7 cells on initiation of Epithelial to Mesenchymal Transition (EMT). Methods. Immunocytochemical analysis, Real-Time PCR, Western blot. Results. We have demonstrated that unbalanced expression of p60, p70 and p85-S6K1 isoforms in MCF-7, namely downregulation of p70 and p85, and basal p60 expression, mediated by the CRISPR-Cas9 gene editing resulted in altered morphology and increased cell motility. Such changes were associated with the expression of genes whose products are involved in the regulation of cell motility, interaction with the extracellular matrix and loss of cellular adhesion demonstrating their increased potential for invasion and metastatic activity. qPCR analysis confirmed increased expression of a whole spectrum of genes associated with mesenchymal characteristics and loss of epithelial specific markers. Additionally, we observed a complete repression of the estrogen receptor 1 (ESR1) expression and downregulation of HER2/NEU (ERBB2). Conclusions. Our data demonstrate for the first time the implication of S6K1 isoforms in the regulation of EMT in MCF-7 cells by triggering for the concomitant onset of a series of possibly parallel events that changes the cell from an epithelial to a mesenchymal type and has a strong negative impact on ESR1 expression. At the tumor level that can mean breast tumor transition to a more aggressive most probably triple negative molecular subtype. [ABSTRACT FROM AUTHOR]

Aim: To identify genomic variants associated with hypo-response to COS in patients with repeated intrauterine insemination (IUI) and/or in vitro fertilization (IVF) failures and devise appropriate management strategies. Materials and methods: Twelve patients with a history of IUI/IVF failures were included in the study. Next generation sequencing (NGS) based genomic analysis on peripheral blood, designed for Indian population was performed to identify risk genotypes. Multiple causative and susceptibility genotypes associated with oogenesis, fertilization, implantation failure, pregnancy loss, premature ovarian insufficiency, oocyte quality, response to COS, and pharmacogenomic correlations were part of the genomic panel. Results: A total of six variants were reported with poor or slow response to controlled ovarian stimulation in AMH, AMHR2, ESR1, FSHR, and LHCGR genes. In two cases, thrombophilia related variants in VEGFA and MTRR genes were also identified. Based on the genotypes identified with ovarian response correlations, stimulation protocols were modified and better outcome was recorded. Conclusion: We demonstrate identification of hypo-responders and customization of controlled ovarian stimulation protocols based on genomic analysis combined with clinical parameters leading to reduction in number of cycles and improving outcome or reproductive success. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to conduct an association analysis of depressive symptoms and polymorphisms in the ESR1, PGR, CYP19A1, and COMT genes in pregnant and postpartum women. Methods: The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for assessment of maternal and fetal health. The German version of the 10-item Edinburgh Postnatal Depression Scale (EPDS) was completed at three time points in this prospective cohort study. Visit 1 was at study entry in the third trimester of pregnancy, visit 2 was shortly after birth, and visit 3 was 6–8 months after birth. Germline DNA and depression measurements from 361 pregnant women were available for analysis. Six single nucleotide polymorphisms (SNPs) in the above-mentioned genes were genotyped. After reconstruction of haplotypes for PGR (rs1042838 and rs10895068) and CYP19A1 (rs10046 and rs4646), a multifactorial linear mixed model was applied to the data to describe the association between haplotypes and depression values. The single SNPs for ESR1 (rs488133) and COMT (rs4680) were analyzed separately using linear mixed models analogously. Results: The mean antepartum EPDS measurement was 5.1, the mean postpartal measurement after 48–72 h was 3.5, and the mean value 6–8 months postpartum was 4.2. The SNPs in PGR were reconstructed into three haplotypes. The most common haplotype was GG, with 63.43% of patients carrying two copies and 33.52% carrying one copy. For haplotype GA, the group of carriers of two copies (0.28%) was combined with the carriers of one copy (9.70%). Haplotype reconstruction using CYP19A1 SNPs resulted in three haplotypes. The most common haplotype was TC, with 25.48% of patients carrying two copies and 51.52% one copy. None of the haplotype blocks and neither of the two single SNPs showed any significant associations with EPDS values. Conclusions: The candidate haplotypes analyzed in PGR and CYP19A1 and single SNPs in ESR1 and COMT did not show any association with depression scores as assessed by EPDS in this cohort of healthy unselected pregnant women. [ABSTRACT FROM AUTHOR]

Background: Mammography Density (MD) is a potential risk marker that is influenced by genetic polymorphisms and can subsequently modulate the risk of breast cancer. This qualitative systematic review summarizes the genes and biological pathways involved in breast density and discusses the potential clinical implications in view of the genetic risk profile for breast density. Methods: The terms related to "Common genetic variations" and "Breast density" were searched in Scopus, PubMed, and Web of Science databases. Gene pathways analysis and assessment of protein interactions were also performed. Results: Eighty-six studies including 111 genes, reported a significant association between mammographic density in different populations. ESR1, IGF1, IGFBP3, and ZNF365 were the most prevalent genes. Moreover, estrogen metabolism, signal transduction, and prolactin signaling pathways were significantly related to the associated genes. Mammography density was an associated phenotype, and eight out of 111 genes, including COMT, CYP19A1, CYP1B1, ESR1, IGF1, IGFBP1, IGFBP3, and LSP1, were modifiers of this trait. Conclusion: Genes involved in developmental processes and the evolution of secondary sexual traits play an important role in determining mammographic density. Due to the effect of breast tissue density on the risk of breast cancer, these genes may also be associated with breast cancer risk. [ABSTRACT FROM AUTHOR]

Abstract Background Progesterone receptor (PGR) is a master regulator of uterine function through antagonistic and synergistic interplays with oestrogen receptors. PGR action is primarily mediated by activation functions AF1 and AF2, but their physiological significance is unknown. Results We report the first study of AF1 function in mice. The AF1 mutant mice are infertile with impaired implantation and decidualization. This is associated with a delay in the cessation of epithelial proliferation and in the initiation of stromal proliferation at preimplantation. Despite tissue selective effect on PGR target genes, AF1 mutations caused global loss of the antioestrogenic activity of progesterone in both pregnant and ovariectomized models. Importantly, the study provides evidence that PGR can exert an antioestrogenic effect by genomic inhibition of Esr1 and Greb1 expression. ChIP-Seq data mining reveals intermingled PGR and ESR1 binding on Esr1 and Greb1 gene enhancers. Chromatin conformation analysis shows reduced interactions in these genes’ loci in the mutant, coinciding with their upregulations. Conclusion AF1 mediates genomic inhibition of ESR1 action globally whilst it also has tissue-selective effect on PGR target genes.

Abstract Background In clinical practice, oestrogen receptor (ER) analysis is almost entirely by immunohistochemistry (IHC). ASCO/CAP recommends cut-offs of

Simple Summary: Secreted Frizzled-Related Protein 1 (SFRP1) expression is decreased during breast cancer progression and inversely associated with breast tissue age-related lobular involution in women. In this study, we have investigated the potential causal role of the decrease in SFRP1 expression in early breast carcinogenesis. In order to do so, we characterized mammary epithelial cells from both nulliparous and multiparous mice in organoid culture ex vivo, and modulated SFRP1 expression in breast non-tumoral and tumoral cell lines from multiple molecular subtypes. Our results support the hypothesis that a lack of SFRP1 could have a causal role in early breast carcinogenesis. A human transcriptome array on ERα-positive breast cancer continuum of risk identified Secreted Frizzled-Related Protein 1 (SFRP1) as decreased during breast cancer progression. In addition, SFRP1 was inversely associated with breast tissue age-related lobular involution, and differentially regulated in women with regard to their parity status and the presence of microcalcifications. The causal role of SFRP1 in breast carcinogenesis remains, nevertheless, not well understood. In this study, we characterized mammary epithelial cells from both nulliparous and multiparous mice in organoid culture ex vivo, in the presence of estradiol (E2) and/or hydroxyapatite microcalcifications (HA). Furthermore, we have modulated SFRP1 expression in breast cancer cell lines, including the MCF10A series, and investigated their tumoral properties. We observed that organoids obtained from multiparous mice were resistant to E2 treatment, while organoids obtained from nulliparous mice developed the luminal phenotype associated with a lower ratio between Sfrp1 and Esr1 expression. The decrease in SFRP1 expression in MCF10A and MCF10AT1 cell lines increased their tumorigenic properties in vitro. On the other hand, the overexpression of SFRP1 in MCF10DCIS, MCF10CA1a, and MCF7 reduced their aggressiveness. Our results support the hypothesis that a lack of SFRP1 could have a causal role in early breast carcinogenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Canine mammary neoplasms commonly lose ERα expression along with an increase in stage and grade, negatively correlating with patient prognosis. The ESR1 gene encodes ERα and represents an important target mRNA for miR-18a and miR-18b, described as overexpressed oncogenes in canine mammary carcinomas. In this study, we demonstrate a negative correlation between the expression of miR-18a and miR-18b and their target ESR1 gene. Notably, a significant overexpression of oncogenic miRNAs was observed in malignant canine mammary tumors (CMTs) compared with the non-neoplastic mammary gland and benign CMTs. In contrast, the expression of target ESR1 mRNA was significantly downregulated along with the increase in tumor grade, and was associated with the progressive loss of ERα immunoexpression. It is noteworthy that the overexpression of miR-18a and miR-18b was observed in malignant tumors with increased proliferation of tumor cells. The results suggest a central role of miR-18a and miR-18b in the pathophysiology of canine mammary tumors, also representing promising biomarkers with predictive and prognostic value. The expression of miRNAs is one of the main epigenetic mechanisms responsible for the regulation of gene expression in mammals, and in cancer, miRNAs participate by regulating the expression of protein-coding cancer-associated genes. In canine mammary tumors (CMTs), the ESR1 gene encodes for ERα, and represents a major target gene for miR-18a and miR-18b, previously found to be overexpressed in mammary carcinomas. A loss in ERα expression in CMTs is commonly associated with poor prognosis, and it is noteworthy that the downregulation of the ESR1 would appear to be more epigenetic than genetic in nature. In this study, the expression of ESR1 mRNA in formalin-fixed, paraffin-embedded (FFPE) canine mammary tumors (CMTs) was evaluated and compared with the expression levels of miR18a and miR18b, both assessed via RT-qPCR. Furthermore, the possible correlation between the miRNA expression data and the immunohistochemical prognostic factors (ERα immunoexpression; Ki67 proliferative index) was explored. A total of twenty-six FFPE mammary samples were used, including 22 CMTs (7 benign; 15 malignant) and four control samples (three normal mammary glands and one case of lobular hyperplasia). The obtained results demonstrate that miR-18a and miR-18b are upregulated in malignant CMTs, negatively correlating with the expression of target ESR1 mRNA. Of note, the upregulation of miRNAs strictly reflects the progressive loss of ERα immunoexpression and increased tumor cell proliferation as measured using the Ki67 index. The results suggest a central role of miR-18a and miR-18b in the pathophysiology of canine mammary tumors as potential epigenetic mechanisms involved in ERα downregulation. Moreover, as miRNA expression reflects ERα protein status and a high proliferative index, miR-18a and miR-18b may represent promising biomarkers with prognostic value. More detailed investigations on a larger number of cases are needed to better understand the influence of these miRNAs in canine mammary tumors. [ABSTRACT FROM AUTHOR]

Background: Uterine fibroids (UFs) are uterine smooth muscle neoplasms that affect women, especially during the reproductive stage. Both genetic and lifestyle factors affect the onset of the disease. We examined the association between the estrogen receptor 1 (ESR1) rs2234693 variant (whose genotypes are TT, TC, and CC) and UFs in Taiwanese premenopausal and postmenopausal women. Methods: We linked individual-level data of 3588 participants from the Taiwan Biobank to the National Health Insurance Research Database at the Health and Welfare Data Science Center. The association of the ESR1 rs2234693 variant and other variables with UFs was determined by multiple logistic regression, and the results were presented as odds ratios and 95% confidence intervals (CIs). Results: The 3588 participants comprised 622 cases and 2966 controls. In all the participants, the ESR1 rs2234693 TC and CC genotypes compared to the reference genotype (TT) were associated with a lower risk of UFs. However, the results were significant only for the CC genotype (OR; 95% CI = 0.70; 0.52–0.93). Noteworthy, the association of TC and CC with UFs was dose-dependent (p-trend = 0.012). Based on menopausal status, both TC and CC were significantly and dose-dependently associated with a lower risk of UFs in premenopausal women (OR; 95% CI = 0.76; 0.59–0.98 for TC and 0.64; 0.43–0.95 for CC: p-trend = 0.010). Conclusion: The TC and CC genotypes of the ESR1 rs2234693 variant may reduce susceptibility to UFs, especially in premenopausal women. [ABSTRACT FROM AUTHOR]

Problem: Protective effects for adult neurological disorders have been attributed to sex hormones. Using a murine model of prematurity, we evaluated the role of estrogen signaling in the process of perinatal brain injury following exposure to intrauterine inflammation. Method of study: Intrauterine lipopolysaccharide (LPS) was used to invoke preterm labor and fetal neuroinflammation. Fetal brains were analyzed for changes in Esr1, Esr2 and Cyp19. Dams heterozygous for the Esr1 knockout allele were also given intrauterine LPS to compare delivery and offspring viability to wild type controls. Results: The upregulation in inflammatory cytokines was accompanied by an increase in Esr1 and Esr2 transcripts, though protein levels declined. Cyp19 did not differ by mRNA or protein abundance. Offspring from Esr1 mutants were larger, had a longer gestation and significantly greater mortality. Conclusions: Estrogen signaling is altered in the fetal brains of preterm offspring exposed to neuroinflammatory injury. The reduction of Esr1 and Esr2 proteins with LPS suggests that these proteins are degraded. It is possible that transcriptional upregulation of Esr1 and Esr2 occurs to compensate for the loss of these proteins. Alternatively, the translation of Esr1 and Esr2 mRNAs may be disrupted with LPS while a feedback mechanism upregulates transcription. Intact Esr1 signaling is also associated with early preterm delivery following exposure to intrauterine LPS. A loss of one Esr1 allele delays this process, but appears to do so at the cost of fetal viability. These results suggest estrogen signaling plays opposing roles between maternal and fetal responses to preterm birth. [ABSTRACT FROM AUTHOR]

Estrogen receptor α (ERα), encoded by the ESR1 gene, is a key prognostic and predictive biomarker firmly established in routine diagnostics and as a therapeutic target of breast cancer, and it has a central function in breast cancer biology. Genetic variants at 6q25.1, containing the ESR1 gene, were found to be associated with breast cancer susceptibility. The rs2046210 and rs9383590 single nucleotide variants (SNVs) are located in the same putative enhancer region upstream of ESR1 and were separately identified as candidate causal variants responsible for these associations. Here, both SNVs were genotyped in a hospital-based case-control study of 409 female breast cancer patients and 422 female controls of a Central European (Austrian) study population. We analyzed the association of both SNVs with the risk, age at onset, clinically and molecularly relevant characteristics and prognosis of breast cancer. We also assessed the concordances between both SNVs and the associations of each SNV conditional on the other SNV. The minor alleles of both SNVs were found to be non-significantly associated with an increased breast cancer risk. Significant associations were found in specific subpopulations, particularly in patients with an age younger than 55 years. The minor homozygotes of rs2046210 and the minor homozygotes plus heterozygotes of rs9383590 exhibited a several-years-younger age at onset than the common homozygotes, which was more pronounced in ER-positive and luminal patients. Importantly, the observed associations of each SNV were not consistently nullified upon correction for the other SNV nor upon analyses in common homozygotes for the other SNV. We conclude that both SNVs remain independent candidate causal variants. [ABSTRACT FROM AUTHOR]

In recent years, Bisphenol S (BPS) has increasingly been used as an alternative to Bisphenol A (BPA) in food, paper, and personal care products. It is imperative to clarify the relationship between BPS and tumors in order to treat and prevent diseases. This study discovered a new method for predicting tumor correlations between BPS interactive genes. According to analyses conducted by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, interactive genes were primarily found in gastric cancer. Based on gene-targeted prediction and molecular docking, BPS appears to exert potential gastric cancer-causing effects through estrogen receptor 1 (ESR1). In addition, gastric cancer patients' prognosis could be accurately predicted by a bisphenol-based prognostic prediction model. Subsequently, the proliferation and migration abilities of gastric cancer cells were further demonstrated to be significantly enhanced by BPS. Similarly, molecular docking analysis revealed that melatonin is also highly correlated with gastric cancer and BPS. In cell proliferation and migration assays, melatonin and BPS exposure inhibited the invasion abilities of gastric cancer cells compared to BPS-exposure. Our research provided a new direction for the exploration the correlation between cancer and environmental toxicity.

ObjectiveThe purpose of this study was to evaluate the effect of estrogen receptor 1 (ESR1) polymorphisms on the development of medication-related osteonecrosis of the jaws (MRONJ) in women with osteoporosis.MethodsA total of 125 patients taking bisphosphonates was evaluated the relationship between MRONJ occurrence and single nucleotide polymorphisms (SNPs) of ESR1. Clinical information was collected, including current age, treatment duration, and comorbidity. Univariate and Multivariable regression analyzes were performed to evaluate the independent predictive factors for MRONJ occurrence. Predictive models were constructed using machine learning methods such as Lasso regression, Random forest (RF), and Support vector machine (SVM). The area under the receiver-operating curve (AUROC) was used to evaluate the performance of a binary classifier.ResultTwo SNPs of ESR1 (rs4870056 and rs78177662) were significantly associated with MRONJ development. Patients with variant allele (A) of rs4870056 showed 2.45 times (95% CI, 1.03–5.87) the odds of MRONJ occurrence compared to those with wild-type homozygote (GG) after adjusting covariates. Additionally, carriers with variant allele (T) of rs78177662 had higher odds than those with wild-type homozygote (CC) (adjusted odds ratio (aOR), 2.64, 95% CI, 1.00–6.94). Among demographic variables, age ≥ 72 years (aOR, 3.98, 95% CI, 1.60–9.87) and bisphosphonate exposure ≥48 months (aOR, 3.16, 95% CI, 1.26–7.93) were also significant risk factors for MRONJ occurrence. AUROC values of machine learning methods ranged between 0.756–0.806 in the study.ConclusionOur study showed that the MRONJ occurrence was associated with ESR1 polymorphisms in osteoporotic women.

Background: An accurate status determination of breast cancer biomarkers (ER, PR, HER2, Ki67) is crucial for guiding patient management. The “gold standard” for assessing these biomarkers in FFPE tissue is IHC, which faces challenges in standardization and exhibits substantial variability. In this study, we compare the concordance of a new commercial RT-qPCR kit with IHC in determining BC biomarker status. Methods: The performance was evaluated using 634 FFPE specimens, which underwent histological analysis in accordance with standard of care methods. HER2 2+ tumors were referred to ISH testing. An immunoreactive score of ≥2/12 was considered positive for ER/PR and 20% staining was used as a cut-off for Ki67 high/low score. RT-qPCR and results calling were performed according to the manufacturer’s instructions. Results: High concordance with IHC was seen for all markers (93.2% for ER, 87.1% for PR, 93.9% for HER2, 77.9% for Ki67 and 80.1% for proliferative signature (assessed against Ki67 IHC)). Conclusions: By assessing the concordance with the results obtained through IHC, we sought to demonstrate the reliability and utility of the kit for precise BC subtyping. Our findings suggest that the kit provides a highly precise and accurate quantitative assessment of BC biomarkers.