Search Results (986)

Background/Objectives: Benign prostatic hyperplasia (BPH) is a common condition in older men and represents a major contributor to lower urinary tract symptoms, prostate enlargement, and features of metabolic syndrome (MetS). Androgen receptor (AR) signaling and extracellular matrix (ECM) remodeling play central roles in BPH pathology, yet the clinical relevance of AR coactivators and structural genes remains incompletely understood. Methods: Prostate tissues from 76 BPH patients and five non-hyperplastic controls were analyzed by quantitative PCR to assess AR coactivators (SRC-1, SRC-2, SRC-3, PCAF, p300) and ECM-related genes (COL1A1, COL3A1). Results: BPH tissues showed marked overexpression of AR coactivators and collagen genes compared to controls (fold changes ≥ 7.8). Higher prostate-specific antigen (PSA) levels (≥10 ng/mL) and enlarged prostate volumes (≥100 mL) were associated with increased expression of PCAF, p300, SRC-1, and COL1A1. PSA and prostate volume correlated positively with triglycerides and VLDL, and inversely with HDL. Strong associations between collagen genes and p160 coactivators suggest coordinated androgenic and stromal remodeling activity. COL1A1 expression was reduced in patients under pharmacological treatment, particularly with alpha-blockers or combination therapies. PCAF and p300 were elevated in patients with MetS, hyperlipidemia, or hyperglycemia. Conclusions: These findings define a molecular signature in BPH linking androgenic, metabolic, and stromal pathology. SRC-1, PCAF, p300, and COL1A1 emerge as potential biomarkers and therapeutic targets, providing new insights into the molecular mechanisms of BPH progression. Full article

In triple-negative breast cancer (TNBC), the clinicopathological significance of the expression of a second estrogen receptor, ERβ, remains unclear. Further, although the clinicopathological significance of mutant p53 and androgen receptor (AR) has been investigated in TNBC, they have not been established as therapeutic targets. Experimental studies reported the importance of cross-talk between ERβ and p53 or AR in TNBC. In this study, we immunohistochemically examined ERβ expression in surgical specimens of TNBC obtained from postmenopausal patients who underwent surgery without neoadjuvant therapy and investigated the relationship between ERβ expression and various clinicopathological factors, including clinical outcome, while also considering p53 and AR. No significant difference in clinical outcome was noted according to the ERβ status alone (p = 0.2908). However, the ERβ status did affect the relationship between the clinical outcome and p53 or AR status; p53-positive or AR-positive group exhibited significantly more favorable clinical outcomes than p53-negative or AR-negative group, respectively, in the ERβ-positive group (p53, p = 0.0265; AR, p = 0.0285), but not in the ERβ-negative group (p53, p = 0.7228; AR, p = 0.7734). This may be the result of a functional interaction between ERβ and p53 or AR. The role of ERβ in TNBC will be elucidated in further complex studies considering multiple molecules. Full article

Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, with disease progression frequently occurring despite the use of potent androgen receptor (AR)-targeted therapies. As AR signalling continues to drive tumour growth in this setting, new therapeutic strategies are being developed to disrupt the AR axis through both direct and indirect mechanisms. This review highlights a selection of promising agents in preclinical or clinical development that represent the next generation of therapies targeting AR signalling. Direct approaches include novel agents that degrade the AR or target domains beyond the conventional ligand-binding domain, aiming to overcome resistance to existing anti-androgens. Indirect strategies are designed to interfere with AR function by modulating AR-associated transcriptional co-regulators, chromatin accessibility, and other regulatory proteins, such as splicing factors, that are critical for sustaining AR-driven gene expression in prostate cancer. Together, these therapies form the basis of emerging strategies to more effectively suppress AR activity in CRPC. This review discusses AR-activating mechanisms, the mechanisms of action of these agents, their clinical development status, and their potential to reshape future treatment paradigms in CRPC. Full article

Triple-Negative Breast Cancer (TNBC) encompasses a biologically heterogeneous group of tumors, which can be classified into distinct molecular subtypes, namely basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR), with unique clinical and pathological characteristics. While immune features of these subtypes have been extensively characterized, the integration of non-immune stromal and structural components into our understanding of TNBC biology is only now being fully recognized. This narrative review synthesizes current evidence regarding differences in the non-immune microenvironment across TNBC molecular subtypes, with a focus on cancer-associated fibroblasts (CAFs), vascular features, extracellular matrix (ECM) dynamics, and epithelial–mesenchymal transition (EMT), along with metabolic–hypoxic reprogramming. Data from several studies are integrated to highlight subtype-specific signatures. Differences in stromal architecture and metabolic adaptations, potentially reflecting the underlying molecular heterogeneity, may hold prognostic or predictive significance and could inform personalized therapeutic strategies targeting the tumor–stroma interface. Full article

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting reproductive-aged women. Previous studies have identified genomic associations at chromosome 12q13.2, but the functional mechanisms underlying these associations remain unclear. We integrated three complementary datasets: (1) WES-identified single nucleotide variants (SNVs) from PCOS and normal theca cells with association testing for forskolin-stimulated androgen production, (2) STARR-seq enhancer activity data with eQTL colocalization analysis, and (3) scRNA-seq expression data comparing forskolin-stimulated PCOS and normal theca cells. We previously identified haplotypes involving 10 SNVs at 12q13.2 containing RPS26/RAB5B/SUOX that are significantly associated with forskolin-stimulated androgen production. The identified haplotypes were further shown to associate with PCOS in a whole genome sequencing (WGS) cohort. Other studies have recently found the enhancer variant rs1081975 demonstrated perfect colocalization (PP = 1.0) with RPS26/RAB5B/SUOX eQTLs. Our scRNA-seq analysis revealed differential expression patterns for key genes. RAB5B showed a forskolin response upregulation in normal cells but an impaired response in PCOS. SUOX exhibited opposite forskolin responses between normal and PCOS cells. PA2G4, an androgen corepressor in the locus, was upregulated in normal untreated cells. ERBB3, an epidermal growth factor receptor in the locus, was downregulated in normal forskolin treated cells. The integration of multimodal genomic data provides functional validation of PCOS-associated variants at 12q13.2, revealing coordinated dysregulation of vesicular trafficking (RAB5B), androgen receptor regulation (PA2G4), and metabolic processes (SUOX) in PCOS theca cells. Full article

Background/Objectives: Rho small GTPases (RSG), which regulates metastasis, constitute eight subfamilies—“classical” Rho, Rac, cdc42, and “atypical” Rif, Rnd, Wrch, RhoH, and RhoBTB. Their downstream signaling requires switching between GTP-bound active and GDP-bound inactive forms. Classical RSGs, but not atypical RSGs, require regulation by guanine nucleotide exchange factors (GEF), GTPase-activating proteins (GAP) and guanine nucleotide dissociation inhibitors (GDI) to achieve this switch. The objective of this review is to summarize the roles of RSGs in metastatic prostate cancer (mPCa) and their interaction with the androgen receptor (AR), which regulates this disease. Methods: We summarize the literature that describes the role of RSGs in mPCa, and their interaction with the AR. Results: Classical RSGs mostly promote metastasis (except RhoB), whereas atypical RSGs, with exceptions, mostly prevent it. Their role, however, is context-dependent—e.g., RhoB is tumor-suppressive in AR-null PCa but oncogenic in AR-positive tumors. The AR modulates RSG expression transcriptionally, but also affects their function through modulation of GEFs, GAPs, and GDIs. In turn, RSGs also regulate AR transcriptional activity. Interestingly, RSGs and the AR have non-genomic interactions via membrane-localized AR (mAR) not affected by AR inhibitors. Conclusions: Drugs that target RSGs are needed along with AR inhibitors to prevent mPCa progression. Full article

Background/Objectives: Prostate cancer is a leading cause of cancer-related morbidity and mortality. While prostate-specific antigen (PSA) is crucial for monitoring, its static levels are limited in predicting outcomes precisely. The Kinetics of Elimination of PSA (KELIM PSA) has recently emerged as a dynamic biomarker of treatment response. This research sought to determine the predictive power of KELIM PSA in castration-resistant prostate cancer (CRPC) on androgen receptor pathway inhibitors (ARPI). Methods: This study retrospectively analyzed 98 CRPC patients treated with enzalutamide or abiraterone. The patients were categorized as either unfavorable (KELIM < 1) or favorable (KELIM ≥ 1). Demographic and clinical characteristics were compared, and survival outcomes were evaluated using Kaplan–Meier curves and Cox regression. Results: Of the cohort, 42 (42.9%) patients had favorable and 56 (57.1%) unfavorable KELIM values. The unfavorable group had a higher mortality rate (62.5% vs. 38.1%, p = 0.029). Univariate analysis showed that poor KELIM results increased mortality risk twofold (hazard ratio [HR]: 2.30, 95% confidence interval [CI]: 1.26–4.19, p = 0.006). In multivariable analysis, unfavorable KELIM remained independently associated with worse overall survival (HR: 2.09, 95% CI: 1.12–3.89, p = 0.020), together with second-line ARPI (HR: 3.19, 95% CI: 1.71–5.93, p < 0.001) and ADT + docetaxel during CSPC (HR: 2.14, 95% CI: 1.11–4.12, p = 0.022). Kaplan–Meier curves revealed that the unfavorable group had notably reduced overall survival and progression-free survival (log-rank p = 0.018). Conclusions: KELIM PSA is an independent predictor in ARPI-treated CRPC. By integrating PSA kinetics into prognostic models, risk stratification may be improved, and this may guide individualized treatment. Prospective multicenter validation is warranted. Full article

Anabolic–androgenic steroids (AAS) are synthetic derivatives of testosterone that are used therapeutically but are frequently abused by athletes and individuals seeking to increase muscle mass. Their anabolic (promoting muscle growth) and androgenic (inducing masculine characteristics) effects result from androgen receptor activation in target tissues. However, chronic supraphysiological AAS exposure is associated with serious cardiovascular consequences, ranging from hypertension and lipid disorders to cardiomyopathy, atherosclerosis, and sudden cardiac death. This review provides an updated and integrative perspective on both the molecular and clinical aspects of AAS-induced cardiovascular toxicity, highlighting recent advances in understanding endothelial injury, oxidative stress, fibrosis, and arrhythmogenesis. Importantly, it emphasizes the emerging recognition of AAS abuse as a modifiable cardiovascular risk factor and discusses potential preventive and therapeutic strategies, including early cardiovascular screening and risk stratification. Understanding these mechanisms is essential for recognizing the clinical manifestations of AAS misuse and for improving cardiovascular risk assessment in affected individuals. These insights underscore the clinical significance of AAS abuse as a cardiovascular risk factor and the need for vigilant cardiac monitoring and early intervention in this population. Full article

Benign prostatic hyperplasia (BPH) and prostatitis are multifactorial urological disorders associated with chronic inflammation, oxidative stress, and androgenic imbalance. Dysphania ambrosioides (L.) Mosyakin & Clemants contains flavonoids and phenolic acids with well-recognised antioxidant and anti-inflammatory properties; however, its potential activity against the molecular targets of these prostatic disorders has not been systematically evaluated. A comparative quantitative analysis was performed using studies published between 2005 and 2025 that reported antioxidant activity (DPPH assay, IC₅₀ in µg/mL) of D. ambrosioides extracts. Metabolites from extracts with IC₅₀ values below the global mean (398.410 ± 81.810 µg/mL; n = 35) were selected for in silico prioritisation using OSIRIS, PASS, and ProTox 3.0, followed by molecular docking (CB-Dock2) against AR, 5AR2, COX-2, NLRP3, and α1A receptors. Luteolin and rosmarinic acid showed favourable binding energies (−9.5 to −7.7 kcal/mol) comparable in magnitude to reference drugs (finasteride −13.4, celecoxib −11.4, tamsulosin −7.3 kcal/mol). These metabolites, exhibited affinity for androgenic, inflammatory, and adrenergic targets, suggesting their potential to modulate key mechanisms underlying both BPH and prostatitis. This study integrates, for the first time, a quantitative assessment of antioxidant activity with a multitarget in silico analysis of D. ambrosioides, prioritising luteolin and rosmarinic acid as natural candidates with potential antioxidant, anti-inflammatory, and antiandrogenic properties relevant to prostatic health. Full article

Prostate cancer (PCa) is the second most common cancer in men, and it is frequently diagnosed at an advanced stage of the disease. Androgen Deprivation Therapy (ADT) has traditionally represented the backbone of therapy for high-risk, recurrent, and metastatic disease; however, in the last ten years a new group of molecules known as androgen receptor pathway inhibitors (ARPIs) have been demonstrated to improve outcomes in metastatic patients when added to ADT. Developed and validated originally in the setting of castration-resistant disease, ARPIs have been implemented progressively earlier in the natural history of PCa, involving patients who have never received ADT before or that are still responsive to this treatment. Considering the strong evidence for treatment intensification in patients with high-risk features, with this review we aim to provide a complete overview of the current indications for the use of ARPIs through all the stages of castration-sensitive prostate cancer (CSPC). Full article

Endocrine-disrupting chemicals (EDCs) are widespread contaminants that interfere with hormonal signaling and compromise reproductive success in aquatic organisms. Vitellogenin (VTG) is one of the most widely established biomarkers of estrogenic exposure, especially in males and juveniles. However, evidence from multi-omics studies indicates that VTG induction occurs within broader transcriptional and regulatory networks, involving genes such as cyp19a1 (aromatase), cyp1a (cytochrome P4501A), and other stress-responsive genes, underscoring the complexity of endocrine disruption. This review focuses on nuclear receptor isoforms, including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and androgen receptor (AR) variants. We examine the diversification of vtg gene repertoires across teleost genomes and epigenetic mechanisms, such as DNA methylation and microRNAs, that modulate sex-dependent sensitivity. In addition, we discuss integrative approaches that combine VTG with transcriptomic, epigenetic, and histological endpoints. Within the Adverse Outcome Pathway (AOP) and weight-of-evidence (WoE) frameworks, these strategies provide mechanistic links between receptor activation and reproductive impairment. Finally, we outline future directions, focusing on the development of sex-specific biomarker panels, the integration of omics-based data with machine learning, and advances in ecogenomics. Embedding molecular responses into ecological and regulatory contexts will help bridge mechanistic insights with environmental relevance and support sustainability goals such as SDG 14 (Life Below Water). Full article

Camel poll gland tissues (PGs) secrete amber liquid and volatile substances during the breeding season, inducing estrus and mating in female camels. These processes are mainly regulated by steroid hormones and their receptors, including the Androgen Receptor (AR). However, the functional components of PGs and their regulatory mechanisms in camel reproduction remain unclear. Therefore, in this study, we identified candidate differentially expressed metabolites (DEMs) and differentially expressed proteins (DEPs) associated with steroids through a multi-omics analysis of PGs during the male camel breeding season. We found that total cholesterol and testosterone concentrations were significantly increased in camel PGs at different stages of the breeding season. DEMs and DEPs related to cholesterol or steroids were analyzed using metabolomics and data-independent acquisition proteomics in the PGs of male Bactrian camels at different stages (early and peak breeding seasons), and the potential mechanism of steroid hormone synthesis was further explored. The metabolomics results identified 13 DEMs related to steroids in PGs at different stages. The proteomics results revealed seven GO terms and 69 DEPs related to steroids, with apolipoprotein E (APOE) identified as the core DEP. Pathway analysis confirmed that APOE and related DEPs were involved in cholesterol and steroid hormone synthesis. Immunostaining showed that APOE and AR were co-localized in the cytoplasm of acinar epithelial cells, and exhibited opposite expression trends in PGs during different breeding stages. These findings demonstrate that APOE- and AR-mediated cholesterol metabolism plays an important role in steroid hormone synthesis during camel reproductive activity, providing valuable insights into the mechanisms of steroid synthesis in PGs. This study offers a theoretical framework for understanding camel reproductive biology, particularly the interplay between APOE and AR in regulating cholesterol metabolism and steroidogenesis. Full article

Although female (XX) and male (XY) placentas generally function the same, it is evident that there are sex-specific postnatal health outcomes following placental dysfunction and pregnancy complications. Although the underlying causes for these sex differences are unclear, it is postulated that differences in XX and XY placental function are involved due to sex chromosomes and/or sex steroids. Studies in breast and prostate cancer cells demonstrated a role for the citrullination enzyme peptidylarginine deiminase 2 (PAD2) in post-translational regulation of estrogen (ESR) and androgen receptor (AR) signaling. The goal of this study is to determine if PAD2 is present in mouse placentas and if XX versus XY differences exist in the relative level of PAD2. Fetuses and placentas were collected from three pregnant mice (C57BL6) at 14 days of gestation. Total RNA and protein were isolated from XX and XY placentas, and relative mRNA and protein were analyzed by real-time PCR and Western blot. AR and PAD2 levels were significantly higher in XY than in XX placentas. This study is the first to demonstrate XX and XY differences in PAD2 and AR in the placenta. It suggests a role for PAD2 regulation of androgen receptor signaling in the XY placenta. Full article

Prostate-specific membrane antigen (PSMA) targeting agents have been the cornerstone of advanced prostate cancer (PCa) management in theranostics due to their high sensitivity for detecting and treating metastatic disease. However, approximately one-third of metastatic castration-resistant PCa (mCRPC) lesions may exhibit low or absent PSMA expression due to tumor heterogeneity, prior androgen deprivation therapy, or loss of androgen receptor expression, subsequently altering their response to PSMA-targeted therapy. The molecular and biological mechanisms underlying PSMA downregulation remain elusive but may include neuroendocrine differentiation or epithelial-to-mesenchymal transition (EMT). This review addresses this knowledge gap by examining recent preclinical and clinical evidence on novel radiotracers with the potential to provide alternative strategies beyond PSMA for imaging and treating PCa. The diagnostic performance and therapeutic potential of three emerging radiotracer classes are discussed, including gastrin-releasing peptide receptor (GRPR) ligands, androgen receptor (AR) ligands, and amino acid analogs. This article further highlights the complementary roles of these radiotracers along with their utility in specific patient populations, such as those with low prostate-specific antigen (PSA), biochemical recurrence (BCR), or confirmed PSMA-negative disease. For instance, GRPR-targeted radiotracers have achieved sensitivity of up to 88% and specificity of up to 90% for detecting primary tumors in PCa. The radiolabeled androgen agonist, fluorine-18 (¹⁸F)-fluoro-5α-dihydrotestosterone (FDHT), has demonstrated 98% true-positive rate in predicting lesions on positron emission tomography (PET) scans of mCRPC patients. On the other hand, the synthetic amino acid analog ¹⁸F-fluciclovine demonstrated a lesion detection rate of 84% for PSA levels at or above 5, and 62.5% for PSA levels ranging from 0.7 to less than 1. This review concludes with future directions on the paradigm of multi-tracer and dual-targeting strategies, which can effectively address challenges associated with PCa tumor heterogeneity and facilitate personalized approaches in theranostics. Full article

Several major cancer types exhibit significant sex dimorphism in incidence and survival. Whether and how sex as a biological factor impacts tumorigenesis, progression, and survival warrants full investigation, as such knowledge may lead to novel, precise prevention and treatment strategies. We reviewed epidemiological and molecular data on sex differences in cancers of the esophagus, bladder, head and neck, lung, liver, kidney, stomach, and skin melanoma, as well as the potential role of androgens and androgen receptor (AR) activity in these cancers. The potential molecular mechanisms are briefly discussed. Elevated testosterone (T) levels seemed to be associated with increased liver cancer and cutaneous melanoma incidences, and with reduced esophageal cancer risk. AR activity does not always correlate with T levels in tumorigenesis and progression. Higher AR expressions are associated with poorer survival in ESCC, whereas the role of AR in the survival of HNSCC and melanoma patients is inconsistent. The molecular impact of AR in liver cancer, kidney cancer, melanoma, and lung cancer is controversial. However, AR is likely to promote tumor growth and/or progression in esophagus, bladder, head and neck, and stomach cancers, and thus is associated with poor survival. Patients diagnosed with a tumor in this latter group could potentially benefit from therapeutic approaches targeting AR. Overall, the research on sex hormone androgens and AR in these cancers is limited. Further research is needed to determine a possible U-shaped relationship of T with cancer risk, and to decipher the role of testosterone and AR in some of these tumors to facilitate our understanding of sex dimorphism and to explore novel T/AR-based treatment options. Full article