Search Results (1,034)

In the late laying phase, laying hens often accumulate fat in their bodies due to high-fat diets, which in turn affects their production performance. Bacillus coagulans has good tolerance in the digestive system and is beneficial to intestinal health. The objective of this study was to evaluate the effect of Bacillus coagulans on production performance, lipid metabolism, and ovarian function in late-phase laying hens. The experiment involved 180 Hy-Line Grey laying hens (65 weeks of age) with similar initial egg production rates. The aged hens were randomly assigned to two treatments with six replicates of 15 hens each. A one-way experimental design was employed: CON group (basal diet) and BC group (basal diet supplemented with 3 × 10⁹ CFU/kg of Bacillus coagulans). The research found that adding Bacillus coagulans to feed significantly reduces ADFI and the feed-to-egg ratio, whilst increasing egg production (p < 0.05). Bacillus coagulans supplementation increased the abundance of Firmicutes and decreased the abundance of Actinobacteriota (p < 0.05), while promoting the proliferation of Lactobacillus and Bacillus (p < 0.05). Furthermore, Bacillus coagulans significantly increased the levels of the bile acids GCDCA, TUDCA, THDCA, LCA, and HDCA in the ileum (p < 0.05). Bacillus coagulans not only increased the activity of T-SOD and CAT in the ovaries, as well as the expression of the Nrf2, HO-1, and SOD1 genes (p < 0.05), but also increased the expression of the estrogen receptor ER-α, FSHR and LHR genes (p < 0.05). In conclusion, dietary supplementation with Bacillus coagulans improved production performance by regulating hepatic lipid metabolism and enhancing ovarian function in aged laying hens. Full article

Background: Hormone receptor-positive breast cancer depends on estrogen and progesterone signaling, yet factors that modulate hormone receptor expression within tumors remain incompletely understood. Human cytomegalovirus (HCMV), a widespread herpesvirus detected in breast tumors, has been associated with reduced expression of estrogen receptor-α (ERα) and progesterone receptor (PR), but a direct causal relationship has not been established. Methods: ER+/PR+ breast cancer cell lines MCF-7 and T47D were infected with HCMV in vitro. ERα and PR protein levels were assessed by immunoblotting, and transcript levels of ESR1 and PGR were quantified by qPCR. To determine whether virus replication was required, parallel experiments used UV-inactivated HCMV. Results: HCMV infection resulted in a marked reduction in ERα and PR protein levels in both cell lines, accompanied by decreased ESR1 and PGR transcript levels by 48 h post-infection. Notably, UV-inactivated HCMV produced a comparable suppression of hormone receptor expression, indicating that viral gene expression and productive replication are not required for this effect. Conclusions: These findings indicate that HCMV exposure suppresses ERα and PR expression in breast cancer cells through a replication-independent mechanism. This effect suggests that viral components or host responses to infection may alter hormone receptor signaling within tumors, with potential implications for hormone receptor signaling and endocrine therapy responsiveness that warrant further investigation. Together, these results identify HCMV as a previously underrecognized modulator of hormone receptor pathways in breast cancer. Full article

Homer proteins (Homer1–3) are scaffold proteins that mediate protein–protein interactions in signal transduction; however, the role of Homer3 in breast cancer (BC), particularly triple-negative breast cancer (TNBC), remains poorly defined. Here, we investigated the clinical relevance and functional significance of Homer3 in BC and TNBC. Publicly available datasets from TCGA and GEO were analyzed to evaluate associations between Homer3 expression and patient outcomes using Kaplan–Meier survival analysis. Pathway enrichment analysis and gene set variation analysis (GSVA) were performed to identify signaling programs associated with Homer3 co-expressed genes. Functional roles were examined using stable TNBC cell lines with Homer3 knockdown or overexpression, followed by assays for cell proliferation, clonogenic growth, migration, invasion, and wound healing. We found that Homer3 expression was elevated in breast tumors compared with normal tissues and was associated with poor prognosis in both BC and TNBC. Homer3 expression was higher in TNBC than in non-TNBC subtypes and negatively correlated with estrogen receptor (ER) and progesterone receptor (PR) expression. Functionally, Homer3 depletion suppressed TNBC cell proliferation, clonogenic capacity, migration, invasion, and wound healing, whereas Homer3 overexpression produced reciprocal effects. Pathway analyses revealed that Homer3 co-expressed genes were enriched in cell cycle-related pathways and Hallmark MYC signaling, which were associated with adverse clinical outcomes. Consistently, Homer3 knockdown selectively reduced key proliferative cell-cycle regulators. Collectively, these findings demonstrate that Homer3 is associated with aggressive phenotypes and MYC- and cell cycle-linked proliferative programs in breast cancer, particularly in TNBC. Survival analyses are presented as exploratory findings, supporting the biological relevance of Homer3 in TNBC. These findings suggest that Homer3 may represent a potential therapeutic vulnerability. Full article

Background/Objectives: Breast cancer biomarker detection through immunohistochemistry (IHC) is essential for treatment planning but faces challenges including turnaround time, variability, and laboratory resource constraints. Large open-source vision-language foundation models offer a potential avenue for inferring biomarker status directly from hematoxylin-and-eosin (H&E)-stained whole-slide images (WSIs). Methods: We evaluated two open-source pathology foundation models—TITAN (Transformer-based Pathology Image and Text Alignment Network, approximately 48.5 M parameters) and CHIEF (Clinical Histopathology Imaging Evaluation Foundation Model, approximately 1.2 M parameters)—for predicting estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status from H&E-stained breast cancer WSIs. WSI data were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma collection (TCGA-BRCA) via the NCI Imaging Data Commons, with biomarker labels from the NCI Genomic Data Commons. In total, 937 cases (995 WSIs; 78.3% ER-positive) were evaluated for ER, 934 cases (992 WSIs; 68.4% PR-positive) for PR, and 646 cases (691 WSIs; 21.1% HER2-positive) for HER2. All evaluation was performed under a strict patient-level 50/25/25 split with 10 independent random partitions; metrics are reported as the mean across partitions with percentile-based 95% confidence intervals. Performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), sensitivity, specificity, and positive predictive value (PPV). Results: TITAN and CHIEF achieved comparable performance for ER (TITAN AUROC: 0.885 [95% CI: 0.848, 0.921], AUPRC: 0.954 [0.940, 0.964]; CHIEF AUROC: 0.877 [0.831, 0.914], AUPRC: 0.955 [0.938, 0.969]) and PR (TITAN AUROC: 0.799, AUPRC: 0.868; CHIEF AUROC: 0.791, AUPRC: 0.864). At the default 0.5 operating point, ER PPV was 0.90 and PR PPV was 0.79–0.81. For HER2, both models achieved AUROC values of 0.71–0.74 and AUPRC values of 0.41–0.45—well above the prevalence-based random baseline (approximately 0.211)—but default-threshold sensitivity was very low (approximately 0.07–0.08), reflecting class imbalance and the use of an uncalibrated default threshold rather than a categorical absence of morphologic signal. Conclusions: Under retrospective evaluation, both models demonstrate strong discriminative performance for ER and moderate performance for PR; HER2 prediction at the default operating point is limited and motivates threshold-calibration and multimodal extensions before any clinical use. AUPRC summarizes precision−recall behavior across thresholds and is distinct from threshold-specific precision (PPV); the two should be reported together for clinical-utility assessment in pathology AI. The findings are hypothesis-generating and motivate prospective external validation across independent institutional cohorts before any clinical deployment is considered. Full article

Estrogens, particularly the most active 17β-estradiol (E2), play a crucial role in the initiation and development of breast cancer. Therefore, current treatment strategies are based on interfering with estrogen receptors (ERs) via pure antiestrogens or selective modulators (SERMs) or by inhibiting estrogen synthesis through key enzymes in this pathway. While SERMs are generally effective, resistance often develops. Moreover, they cannot be used to treat triple-negative breast cancers (TNBCs). Three critical enzymes in the estrogen synthesis pathway, namely aromatase, sulfatase, and 17β-hydroxysteroid dehydrogenases, are of particular interest as drug targets. Some, such as aromatase inhibitors, are already used in clinical practice, while the other two remain under intensive investigation. Several comprehensive reviews have been published on ER modulators or individual enzyme inhibitors. This paper attempts to summarize recent data on modulators/inhibitors of both the ER and the major enzymes involved in estrogen biosynthesis and offers a perspective on their further development. Full article

11-ketotestosterone (11-KT) has previously been shown to promote previtellogenic ovarian development and vitellogenin-related hepatic responses in sterlet (Acipenser ruthenus), but the endocrine genes involved in this process remain unclear. In this study, previtellogenic female sterlets were implanted with slow-release 11-KT strips at 5 or 25 mg/kg for 30 days, and transcriptional responses of HPG-axis-related genes, including GnRH paralogs, gonadotropins, and gonadotropin receptors, were examined in the brain-pituitary complex, liver, and ovary. In the brain-pituitary complex, 11-KT increased fsh expression in the 25 mg/kg group and upregulated fshr in both treatment groups, whereas gnrh paralogs showed limited responses. In the liver, most GnRH- and gonadotropin-related genes were not significantly altered, suggesting that hepatic expression of upstream reproductive-axis genes was not a major in vivo target of 11-KT feedback. The ovary exhibited the strongest response, with increased gnrh2 and fsh expression and reduced gnrh3, fshr, and lhr expression, especially at the higher dose. To further examine receptor-related regulation of hepatic vtg expression, liver tissue was incubated in vitro with 11-KT alone or in combination with the androgen receptor antagonist flutamide or the estrogen receptor antagonist fulvestrant. Flutamide did not abolish 11-KT-induced vtg expression, whereas high-dose fulvestrant reduced both era and vtg expression relative to 11-KT treatment alone. Overall, 11-KT elicited tissue-specific transcriptional responses in HPG-axis-related genes, particularly involving ovarian gnrh2, fsh, fshr, and lhr. The differential antagonist responses observed in liver explants provide in vitro evidence consistent with the involvement of ER-associated signaling in hepatic vtg expression, but do not establish direct receptor-mediated regulation. Full article

Estrogen receptor (ER)-positive breast cancer (BrCa) accounts for two-thirds of all BrCa cases worldwide. Therefore, ER-targeted endocrine therapy is the standard treatment for this disease. There has been a recent trend towards developing combination therapies using molecularly targeted drugs to improve outcomes. This study aimed to identify therapeutic targets demonstrating efficacy when combined with fulvestrant (a selective ER downregulator/degrader). We generated microRNA (miRNA) signatures from fulvestrant-treated MCF-7 cells by RNA sequencing. From the signature, we evaluated miR-374b-5p because its expression was elevated by fulvestrant treatment in MCF-7 cells. Also, in expression analysis by subtype of BrCa patients, miR-374b-5p expression was suppressed only in luminal BrCa. Ectopic expression assays revealed that miR-374b-5p attenuated the malignant phenotypes of MCF-7 cells. We searched for genes regulated by miR-374b-5p and discovered that 11 (NEK2, NUF2, HMMR, DEPDC1B, FOXM1, ELOVL6, KIF20A, NCAPH, CENPK, FAM83D, and KIAA0101) are closely involved in BrCa molecular pathogenesis. Among these target genes, we focused on forkhead box M1 (FOXM1), a transcription factor regulating cell cycle progression and division. Notably, combination therapy with fulvestrant and a FOXM1 inhibitor significantly suppressed MCF-7 cell proliferation. From the miRNA signature established in this study, we identified antitumor miR-374b-5p and its target genes and used these findings to explore candidate drugs with potential efficacy when combined with fulvestrant. Full article

Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC) is the most prevalent subtype of advanced breast cancer and is predominantly driven by estrogen receptor (ER) signaling. Endocrine therapy (ET) has become the backbone of first-line treatment; however, both intrinsic and acquired resistance limit long-term disease control. The introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has fundamentally reshaped the therapeutic landscape even in subsets of patients with aggressive or symptomatic visceral metastatic disease. Advances in molecular profiling have also enabled more precise, adaptive therapy. Circulating tumor DNA (ctDNA)-based liquid biopsy now allows real-time detection of emerging resistance mutations, particularly in ESR1. Additionally, patients with PIK3CA-mutated tumors who had progressed on or within 12 months of completing adjuvant ET and had no prior systemic therapy for metastatic disease had better treatment outcomes when treated with the PI3K inhibitor inavolisib in combination with palbociclib and fulvestrant. Together, these developments mark a shift from fixed treatment sequencing toward a more dynamic, biomarker-driven approach in first-line HR+/HER2– MBC. Integration of CDK4/6 inhibitors with next-generation endocrine agents and liquid biopsy-guided therapy offers the potential to delay resistance, improve survival outcomes, and individualize treatment. Full article

Breast cancer (BC) is a major global public health problem. Classical therapies have limited success on the treatment of BC; therefore, new therapeutic options are needed. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that represent a revolutionary class of new drug candidates because they induce the degradation of harmful, undruggable proteins by activating the ubiquitination machinery of cells. Their unique mechanism of action offers several advantages over conventional drugs, but also disadvantages, as most of them are large molecules with unfavorable pharmacokinetic properties, which limits their bioavailability. Vepdegestrant (Veppanu^TM) is an orally administered, estrogen receptor (ER) targeting chimera that was approved by the FDA on 1 May 2026, for the treatment of adults with ESR1-mutated advanced or metastatic breast cancer. Thus, vepdegestrant became the first-ever approved PROTAC drug. In this article, we briefly summarize the structure, mechanism of action, and key available pharmacokinetic and pharmacological data of vepdegestrant. Full article

Triple negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer characterized by the absence of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), resulting in limited options for targeted therapy and high rates of metastasis, recurrence and death. Extracellular vesicles (EVs) have emerged as central mediators of TNBC pathophysiology, functioning as key intercellular communication vehicles transporting oncogenic proteins, nucleic acids, lipids, and metabolites. These EV-mediated interactions promote tumor microenvironment (TME) remodeling, immune evasion, metastatic niche formation, and therapeutic resistance. Given their stability, accessibility, and molecular complexity, EVs also represent promising diagnostic and prognostic biomarkers for TNBC. Advances in isolation and molecular profiling technologies have enabled the identification of EV-associated signatures that predict therapeutic response and stratify patient risk. Beyond their utility as biomarkers, EVs are rapidly emerging as therapeutic targets and delivery platforms, demonstrating efficacy in transporting chemotherapeutics, RNA-based therapeutics, immune modulators, and photosensitizers with enhanced targeting specificity and therapeutic efficiency. Collectively, EVs play a multifaceted role in TNBC biology, serving simultaneously as drivers of disease progression, minimally invasive biomarkers, and versatile therapeutic vehicles. The integration of EV-centered diagnostics, multi-omic profiling, and engineered therapeutics holds significant potential to transform TNBC management and advance precision oncology for this challenging breast cancer subtype. Full article

Background: Several novel oral estrogen receptor (ER) degraders have been shown to modestly improve progression-free survival (PFS) compared to standard endocrine therapy (ET) in patients carrying ESR1 mutations. However, whether overall survival (OS) is also improved is unknown. Methods: All randomized controlled trials (RCTs) comparing ER degraders to standard ET in patients with ER+HER2-metastatic breast cancer were identified. The efficacy outcomes included PFS and OS for the intention-to-treat (ITT) population and were stratified according to ESR1 status (mutated versus wildtype). Hazard ratios (HRs) and 95% confidence intervals (CIs) for PFS and OS were extracted and pooled into a meta-analysis. Results: Eight RCTs comprising 4230 patients were analyzed. Compared to standard ET, ER degraders were associated with statistically significant improvement in OS in the ITT population, with HR 0.81, 95% CI 0.69–0.95, p = 0.01. Analysis by ESR1 status demonstrated that ER degraders were associated with significant improvement in the OSs for patients with an ESR1 mutation (HR = 0.70, 95% CI 0.56–0.88, p = 0.002), but not for patients with ESR1 wildtype (HR = 0.88, 95% CI 0.68–1.13, p = 0.32). ER degraders were associated with a significant improvement in PFS in the ITT population, with HR 0.81, 95% CI 0.68–0.96, p = 0.02. Significant improvement in PFS was found for patients with an ESR1 mutation (HR 0.55, 95% CI 0.45–0.68, p < 0.0001), but not for patients with the ESR1 wildtype (HR 0.97, 95% CI 0.86–1.09, p = 0.61. Conclusions: Compared to standard ET, ER degraders were associated with statistically significant improvement in OS and PFS. Subgroup analyses confirmed that the benefit is limited to patients with ESR1 mutations. Full article

Selective androgen receptor modulators (SARMs) are commonly described as tissue-selective anabolic agents, yet the extent to which this selectivity is reflected at the level of receptor-binding energetics remains uncertain. This study evaluated the receptor interaction profiles of the steroidal SARM YK11 and the nonsteroidal SARM ostarine across five steroid hormone nuclear receptors. Flexible molecular docking was performed with AutoDock 4.2 against the androgen (AR), estrogen (ER), progesterone (PR), glucocorticoid (GR), and mineralocorticoid (MR) receptors, using testosterone, estradiol, progesterone, cortisol, and aldosterone as endogenous reference ligands. Binding free energy, docking-derived inhibition constants, intermolecular interaction energies, conformational sampling, and two-dimensional interaction maps were analyzed. Ostarine showed favorable binding across all receptor systems, with binding energies ranging from −10.42 to −12.05 kcal/mol and no pronounced energetic preference for the androgen receptor. YK11 displayed stronger predicted binding, particularly toward the glucocorticoid, progesterone, and androgen receptors, with a docking energy trend of GR > PR > AR > MR > ER. Interaction analysis revealed conserved polar anchoring residues across receptor pockets, together with scaffold-specific contacts that may explain cross-receptor compatibility. These findings indicate that, within the AutoDock 4.2 flexible docking framework applied in this study, docking-derived binding energies primarily describe thermodynamic compatibility with nuclear receptor ligand-binding domains and should not be interpreted as direct predictors of functional SARM tissue selectivity. The observed discordance between predicted receptor affinity and the established tissue-selective pharmacology of ostarine highlights the need for caution when using single-method docking workflows to infer selectivity among closely related steroid hormone receptors. The novelty of this study lies in demonstrating, using a defined AutoDock 4.2-based comparative protocol, that receptor-binding energetics alone do not recapitulate the functional tissue-selective behavior attributed to SARMs. Full article

Endometriosis is a long-term gynecological condition marked by the growth of endometrial-like tissue outside the uterus, which undergoes proliferation, bleeding, and regeneration. This disease is associated with disrupted steroid hormone signaling, notably progesterone (P4) resistance and estradiol (E2) dominance. P4 resistance has been associated with impaired activation of the progesterone receptor (PR) and reduced transcription of P4 target genes, while elevated E2 levels induce estrogen receptor (ER)-mediated signaling, enhancing estrogen-dependent lesion growth. This hormonal imbalance contributes to a pro-inflammatory microenvironment, chronic pelvic pain, infertility, and enhanced neuroangiogenesis. Emerging evidence indicates that the coordinated regulation of neurotrophins and sex hormones promotes nerve fibers and blood vessel growth and invasion within endometriotic lesions. P4 and E2 have been shown to modulate the expression of key neurotrophins, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). This review presents current evidence on the interplay between neurotrophins and ovarian steroids in endometriosis, with a specific focus on their contribution to neuroangiogenesis and pain pathophysiology. The review includes articles in English containing the Medical Subject Headings (MeSH) terms: “endometriosis”, “neurotrophins”, “nerve growth factor”, “brain-derived neurotrophic factor”, “neuroangiogenesis”, “progesterone”, and “estradiol”, found in the PubMed database published between 2000 and 24 May 2026. This review included a range of original research articles, systematic reviews, meta-analyses, prospective observational studies, case–control studies, and review papers, for a total of 122 articles. Full article

Triple-positive breast cancer (TPBC) is characterized by the overexpression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), making its management a therapeutic challenge. Despite the availability of targeted therapies, patients with TPBC often experience recurrence and poor clinical outcomes due to intrinsic and acquired resistance mechanisms. This review summarizes current therapeutic approaches and their limitations, highlights the molecular mechanisms underlying treatment resistance and recurrence, and explores opportunities for drug repurposing, particularly involving multi-target inhibitors. Special emphasis is placed on the interaction between hormone receptor and growth factor receptor pathways, compensatory signaling mechanisms, and predictive biomarkers of recurrence. Furthermore, emerging strategies for drug repurposing using clinically available drugs are analyzed, including in silico, in vitro, and clinical trial evidence, along with their translational implications. Finally, we conclude that drug repurposing and multi-target approaches offer a compelling rationale for the development of novel therapeutic strategies in triple-positive breast cancer. However, their clinical utility remains to be validated through appropriately designed experimental and clinical studies before their impact on recurrence outcomes can be established. Full article

Triple-negative breast cancer (TNBC), characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is a highly aggressive molecular subtype with high recurrence and metastasis rates. Due to the absence of reliable molecular targets, surgery combined with chemotherapy remains the mainstay of clinical treatment. In recent years, immunotherapy has provided new strategies for TNBC management. Immune checkpoints are key regulatory molecules that maintain immune homeostasis, and blocking these checkpoints can restore T cell activity and enhance tumor cell killing. Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit, particularly in combination with chemotherapy for patients with locally advanced or metastatic TNBC. This review focuses on immune checkpoint–based immunotherapy in TNBC, providing an overview from mechanistic insights to clinical applications and emerging therapeutic strategies. In addition to ICIs, we discuss alternative approaches, such as bispecific antibodies, antibody–drug conjugates (ADCs), chimeric antigen receptor T cell (CAR-T) therapy, tumor vaccines, and oncolytic viruses (OVs), highlighting their current research progress and clinical applications in TNBC treatment. Full article