Genomic analysis uncovers that cold-inducible RNA binding protein is associated with estrogen receptor in breast cancer.

BACKGROUND: RNA-binding proteins (RBPs) perform various biological functions in humans and are associated with several diseases, including cancer. Therefore, RBPs have emerged as novel therapeutic targets. Although recent investigations have shown that RBPs have crucial functions in breast cancer (BC), detailed research is underway to determine the RBPs that are closely related to cancers. OBJECTIVE: To provide an insight into estrogen receptor (ER) regulation by cold-inducible RNA binding protein (CIRBP) as a novel therapeutic target. RESULTS: By analyzing the genomic data, we identified a potential RBP in BC. We found that CIRBP is highly correlated with ER function and influences clinical outcomes, such as patient survival and endocrine therapy responsiveness. In addition, CIRBP influences the proliferation of BC cells by directly binding to ER-RNA. CONCLUSION: Our results suggest that CIRBP is a novel upstream regulator of ER and that the interplay between CIRBP and ER may be associated with the clinical relevance of BC.

Effects and Mechanism of Morinda Officinalis How on Metabolism-Associated Fatty Liver Disease.

AIMS: This study aims to investigate the effects and mechanism of Morinda Officinalis How (MOH), a lianoid shrub with potential therapeutic properties, on Metabolism- Associated Fatty Liver Disease (MAFLD). bjective: The objective of this study was to construct a MOH-MAFLD network prediction model and explore the effect of MOH on MAFLD and its underlying mechanism in vivo. METHODS: Screening of MAFLD targets was performed using the DisGeNET database. Venny database was used to establish the MOH-MAFLD interaction network map, while the STRING database was applied to assess the Protein-Protein Interaction (PPI) network. The central target gene was screened using Gene Ontology (GO) function analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. RESULTS: GO function enrichment analysis revealed that MOH affected MAFLD through apoptosis and estrogen-related pathways. KEGG pathway enrichment and PPI network analysis indicated that MOH might mitigate MAFLD by reducing apoptosis and improving lipid metabolism. Additionally, 6 weeks of MOH treatment in rats decreased caspase-3 levels and increased Bcl-2, Estrogen receptor α(Esr1), and JUN proteins, thus ameliorating MAFLD progression. CONCLUSION: MOH could delay the progression of MAFLD by affecting estrogen-related pathways, reducing cell stress, and inhibiting apoptosis.

Cardamomin Inhibits the Proliferation and Tumorigenesis of Bladder Cancer by ESR1 in PI3K/AKT Pathway.

Cardamomin has been widely studied in cancer, but its role in cancer bladder cancer has not been mentioned. In this study, we validated the anti-cancer effect of cardamom and whether its potential mechanism is related to the PI3K/AKT pathway. After treating with different doses of cardamomin, the cytotoxicity was studied by CCK8. Secondly, we analyzed the effect of cardamomin on the proliferation, apoptosis and cell movement. Next, we analyzed the regulation of ESR1 by western blot and its impact on the PI3K/AKT pathway. We also transfected ESR1 overexpression and silencing vectors, and verified the transfection efficiency through RT-qPCR. Further, the specific mechanism of the drug's inhibitory effect on bladder cancer was also determined. We constructed the subcutaneous tumor model in vivo. After cardamomin administration, we mainly analyzed the positive expression of KI67 in tumor tissues by immunohistochemistry, and the apoptotic cells in tumor tissues by TUNEL, and related proteins in PI3K/AKT pathway by western blot. In this paper, cardamomin inhibited cell proliferation and invasion ability, blocked the transition of G0/G1 phase to S phase, and increased apoptotic rate of 5637 and HT1376 cells, as well as raised ESR1 expression. Cardamomin exerted anti-tumor effect through PI3K/AKT pathway. In vivo animal experiments indicated the inhibitory effect of cardamomin on subcutaneous implanted tumor. Cardamomin inhibited the positive expression of KI67 and promoted the TUNEL-positive cells in tumor tissues. Consistent with in vitro assay, cardamomin increased the expression of ESR1 and downregulated the PI3K/AKT pathway. Cardamomin has a significant inhibitory effect on bladder cancer, and upregulate the expression of ESR1 in bladder cancer through PI3K/AKT.

Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice.

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%.

Standardized molecular pathology workflow for ctDNA-based ESR1 testing in HR+/HER2- metastatic breast cancer.

Mutations in the estrogen receptor alpha gene (ESR1) can lead to resistance to endocrine therapy (ET) in hormone receptor-positive (HR+)/ HER2- metastatic breast cancer (MBC). ESR1 mutations can be detected in up to 40 % of patients pretreated with ET in circulating tumor DNA (ctDNA). Data from prospective randomized trials highlight those patients with HR+/HER2- MBC with detectable ESR1 mutations experience better outcomes when receiving novel selective estrogen receptor degraders (SERDs). There is a high need for optimizing ESR1 testing strategies on liquid biopsy samples in HR+/HER2- MBC, including a hugh quality workflow implementation and molecular pathology reporting standardization. Our manuscript aims to elucidate the clinical and biological rationale for ESR1 testing in MBC, while critically examining the currently available guidelines and recommendations for this specific type of molecular testing on ctDNA. The objective will extend to the critical aspects of harmonization and standardization, specifically focusing on the pathology laboratory workflow. Finally, we propose a clear and comprehensive model for reporting ESR1 testing results on ctDNA in HR+/HER2- MBC.

Next generation selective estrogen receptor degraders in postmenopausal women with advanced-stage hormone receptors-positive, HER2-negative breast cancer.

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 advanced-stage 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.

Columnar Cell Thyroid Carcinoma: A Heterogeneous Entity Demonstrating Overlap Between Papillary Thyroid Carcinoma and Follicular Neoplasms.

BACKGROUND: Columnar cell papillary thyroid carcinoma (CC-PTC) is a morphologic subtype of papillary thyroid carcinoma with a variable prognosis. It is characterized by neoplastic thyroid follicular-derived cells with pseudostratified columnar morphology arranged in papillary or follicular structures with supranuclear or subnuclear vacuoles. The molecular profile of this subtype has only recently come under scrutiny, with mixed results. The aim of this study is to further explore the morphologic, immunohistochemical, and genetic profile of CC-PTC, as well as to correlate these features with clinical outcomes. METHODS: CC-PTC cases were identified from 3 institutions. Immunohistochemistry (ER, CDX2) and molecular testing (DNA and RNA sequencing) were performed. Clinicopathologic parameters and patient outcomes were recorded. RESULTS: Twelve cases (2006-2023) were identified, all in adults (age 45-91). Two presented with disease outside the thyroid gland (neck and mediastinum) and two presented with distant metastasis. Four were high-grade differentiated thyroid carcinomas (necrosis or mitoses), one of which died of disease. Four were noninvasive or minimally invasive, one of which locally recurred. Three patients had lymph node metastases. ER and CDX2 were positive in 73% and 50%, respectively. Pathogenic mutations were found in TERT promoter (n = 3), RAS (n = 2), ATM, NOTCH1, APC, and ESR1, along with cases bearing AGK::BRAF fusion (n = 1), BRAF VE1 expression (n = 1), and NF2 loss (n = 1). CONCLUSIONS: This study represents the largest molecularly defined cohort of non-oncocytic thyroid carcinomas with columnar cell morphology. These tumors represent a genetically and behaviorally heterogeneous group of neoplasms, some of which have RAS-like or follicular neoplasm-like genetics, some of which have BRAF-p.V600E-like or classic papillary thyroid carcinoma-like genetics, and some of which remain unclear. Noninvasive or minimally invasive tumors showed an indolent course compared to those with angioinvasion, gross extrathyroidal growth, or high-grade morphology. Consideration could be given to reclassification of this neoplasm outside of the subtyping of papillary thyroid carcinoma in light of its genetic diversity, distinct morphology, and clinical behavior more closely aligned with follicular thyroid neoplasms.

Computational framework for identifying and evaluating mutagenic and xenoestrogenic potential of food additives.

Food additives are chemicals incorporated in food to enhance its flavor, color and prevent spoilage. Some of these are associated with substantial health hazards, including developmental disorders, increase cancer risk, and hormone disruption. Hence, this study aimed to comprehend the in-silico toxicology framework for evaluating mutagenic and xenoestrogenic potential of food additives and their association with breast cancer. A total of 2885 food additives were screened for toxicity based on Threshold of Toxicological Concern (TTC), mutagenicity endpoint prediction, and mutagenic structural alerts/toxicophores identification. Ten food additives were identified as having mutagenic potential based on toxicity screening. Furthermore, Protein-Protein Interaction (PPI) analysis identified ESR1, as a key hub gene in breast cancer. KEGG pathway analysis verified that ESR1 plays a significant role in breast cancer pathogenesis. Additionally, competitive interaction studies of the predicted potential mutagenic food additives with the estrogen receptor-α were evaluated at agonist and antagonist binding sites. Indole, Dichloromethane, Trichloroethylene, Quinoline, 6-methyl quinoline, Ethyl nitrite, and 4-methyl quinoline could act as agonists, and Paraldehyde, Azodicarbonamide, and 2-acetylfuranmay as antagonists. The systematic risk assessment framework reported in this study enables the exploration of mutagenic and xenoestrogenic potential associated with food additives for hazard identification and management.

Estrogen Receptor Alpha Mutations, Truncations, Heterodimers, and Therapies.

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.

In silico and network pharmacology analysis of fucosterol: a potent anticancer bioactive compound against HCC.

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.

Androgen receptor and estrogen receptor variants in prostate and breast cancers.

The androgen receptor (AR) and estrogen receptor alpha (ERα) are steroid receptor transcription factors with critical roles in the development and progression of prostate and breast cancers. Advances in the understanding of mechanisms underlying the ligand-dependent activation of these transcription factors have contributed to the development of small molecule inhibitors that block AR and ERα actions. These inhibitors include competitive antagonists and degraders that directly bind the ligand binding domains of these receptors, luteinizing hormone releasing hormone (LHRH) analogs that suppress gonadal synthesis of testosterone or estrogen, and drugs that block specific enzymes required for biosynthesis of testosterone or estrogen. However, resistance to these therapies is frequent, and is often driven by selection for tumor cells with alterations in the AR or ESR1 genes and/or alternatively spliced AR or ESR1 mRNAs that encode variant forms AR or ERα. While most investigations involving AR have been within the context of prostate cancer, and the majority of investigations involving ERα have been within the context of breast cancer, important roles for AR have been elucidated in breast cancer, and important roles for ERα have been elucidated in prostate cancer. Here, we will discuss the roles of AR and ERα in breast and prostate cancers, outline the effects of gene- and mRNA-level alterations in AR and ESR1 on progression of these diseases, and identify strategies that are being developed to target these alterations therapeutically.

Gene expression markers in peripheral blood and outcome in patients with platinum-resistant ovarian cancer: A study of the European GANNET53 consortium.

Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum-resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20-2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk-reducing effect (CDH1 HR 0.66, 95% CI: 0.46-0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39-0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1-presence and ESR1-absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08-39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients.

The Treatment of Tubal Inflammatory Infertility using Yinjia Tablets through EGFR/MEK/ERK Signaling Pathway based on Network Pharmacology.

Background: Salpingitis obstructive infertility (SOI) refers to infertility caused by abnormal conditions such as tubal adhesion and blockage caused by acute and chronic salpingitis. SOI has a serious impact on women's physical and mental health and family harmony, and it is a clinical problem that needs to be solved urgently.

Objective: The purpose of the present study was to explore the potential pharmacological mechanisms of the Yinjia tablets (Yin Jia Pian, YJP) on tubal inflammation.

Methods: Networks of YJP-associated targets and tubal inflammation-related genes were constructed through the STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of YJP were identified using Cytoscape and Database for Annotation, Visualization, and Integrated Discovery (metascape). E. coli was used to establish a rat model of tubal inflammation and to validate the predictions of network pharmacology and the therapeutic efficacy of YJP. H&E staining was used to observe the pathological changes in fallopian tubes. TEM observation of the ultrastructure of the fallopian tubes. ELISA was used to detect the changes of IL-6 and TNF-α in fallopian tubes. Immunohistochemistry was used to detect the expression of ESR1. The changes of Bcl-2, ERK1/2, p-ERK1/2, MEK, p-MEK, EGFR, and p-EGFR were detected by western blot.

Results: Through database analysis, it was found that YJP shared 105 identical targets with the disease. Network pharmacology analysis showed that IL-6, TNF, and EGFR belong to the top 5 core proteins associated with salpingitis, and EGFR/MEK/ERK may be the main pathway involved. The E. coli-induced disease rat model of fallopian tube tissue showed damage, mitochondrial disruption, and increased levels of the inflammatory factors IL-6 and TNF-α. Tubal inflammatory infertility rats have increased expression of Bcl-2, p-ERK1/2, p-MEK, and p-EGFR, and decreased expression of ESR1. In vivo, experiments showed that YJP improved damage of tissue, inhibited shedding of tubal cilia, and suppressed the inflammatory response of the body. Furthermore, YJP inhibited EGFR/MEK/ERK signaling, inhibited the apoptotic protein Bcl-2, and upregulated ESR1.

Conclusion: This study revealed that YJP Reducing tubal inflammation and promoting tissue repair may be associated with inhibition of the EGFR/MEK/ERK signaling pathway.

Ovaries of estrogen receptor 1-deficient mice show iron overload and signs of aging.

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.

The Potential Mechanism of Liujunzi Decoction in the Treatment of Breast Cancer based on Network Pharmacology and Molecular Docking Technology.

BACKGROUND: Liujunzi Decoction (LJZD) is a potential clinical treatment for Breast Cancer (BC), but the active ingredients and mechanisms underlying its effectiveness remain unclear. OBJECTIVE: The study aimed to investigate the target gene of LJZD compatibility and the possible mechanism of action in the treatment of breast cancer by using network pharmacology and molecular docking. METHODS: Based on TCMSP, ETCM, and BATMAN database searching and screening to obtain the ingredients of LJZD, the related targets were obtained. Breast cancer-related targets were collected through GEO, Geencards, OMIM, and other databases, and drug-disease Venn diagrams were drawn by R. The PPI network map was constructed by using Cytoscape. The intersecting targets were imported into the STRING database, and the core targets were analyzed and screened. The intersected targets were analyzed by the DAVID database for GO and KEGG enrichment. AutoDock Vina and Gromacs were used for molecular docking and simulation of the core targets and active ingredients. RESULTS: 126 active ingredients of LJZD were obtained; 241 targets related to breast cancer were sought after screening, and 180 intersection targets were identified through Venn diagram analysis. The core targets were FOS and ESR1. KEGG enrichment analysis mainly involved PI3K/Akt, MAPK, and other signaling pathways. CONCLUSION: This study has explored the possible targets and signaling pathways of LJZD in treating breast cancer through network pharmacology and bioinformatics analysis. Molecular docking and simulation have further validated the potential mechanism of action of LJZD in breast cancer treatment, providing essential experimental data for future studies.

Comprehensive and Accurate Molecular Profiling of Breast Cancer through mRNA Expression of ESR1, PGR, ERBB2, MKI67, and a Novel Proliferation Signature.

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.

The clinical impact of plasma estrogen receptor-1 mutation in patients with metastatic breast cancer: A meta-analysis.

BACKGROUND: The relevance of the discovered plasma ESR1 mutations in positive metastatic breast cancer (BC) patients who had progressing disease after aromatase inhibitor (AI)-based therapy is still being debated. OBJECTIVES: We conducted this meta-analysis to explore the prognostic and predictive role of plasma ESR1 mutations in patients with progressive BC who have previously received AI therapy. MATERIAL AND METHODS: We searched for relevant studies in the PubMed, Embase and Cochrane Library databases to be included in the meta-analysis. This study was performed to compute combined hazard ratios (HRs) with 95% confidence intervals (95% CIs) for the progression-free survival (PFS) rate and overall survival (OS) rate. Subgroup and sensitivity analyses were also performed. The heterogeneity between studies was evaluated using the I2 statistic. RESULTS: In this meta-analysis, a total of 1,844 patients with metastatic BC and positive for estrogen receptors (ERs) were enrolled from 8 articles. The analysis revealed that patients with circulating ESR1 mutations had significantly worse PFS (HR: 1.34; 95% CI: 1.17-1.55; p < 0.001) and OS (HR: 1.59; 95% CI: 1.31-1.92; p < 0.001) compared to wild-type ESR1 patients. Subgroup analysis showed that the types of plasma ESR1 mutations were associated with differences in the prognosis of metastatic BC. The D538G mutation showed a statistically significant lower PFS (p = 0.03), while the Y537S mutation was not significantly correlated with PFS (p = 0.354). CONCLUSION: According to the findings of this meta-analysis, the assessment for plasma ESR1 mutations may provide prognostic and clinical guidance regarding subsequent endocrine therapy decisions for ER-positive, metastatic BC patients who had received prior therapy with AIs.

Locus-level L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites.

Long interspersed element 1 (L1) retrotransposons are implicated in human disease and evolution. Their global activity is repressed by DNA methylation, but deciphering the regulation of individual copies has been challenging. Here, we combine short- and long-read sequencing to unveil L1 methylation heterogeneity across cell types, families, and individual loci and elucidate key principles involved. We find that the youngest primate L1 families are specifically hypomethylated in pluripotent stem cells and the placenta but not in most tumors. Locally, intronic L1 methylation is intimately associated with gene transcription. Conversely, the L1 methylation state can propagate to the proximal region up to 300 bp. This phenomenon is accompanied by the binding of specific transcription factors, which drive the expression of L1 and chimeric transcripts. Finally, L1 hypomethylation alone is typically insufficient to trigger L1 expression due to redundant silencing pathways. Our results illuminate the epigenetic and transcriptional interplay between retrotransposons and their host genome.