Search Results (66)

Background: ERβ is an estrogen receptor isoform expressed in the normal human colon and has been proposed to act as a tumor suppressor gene. The loss of ERβ expression has been associated with advanced stages of CRC. The aim was to investigate the relationship between ERβ expression and CRC progression, quantifying the difference between tumor tissues and normal controls, and early-stage versus late-stage tumors. Methods: English Medical literature searches were conducted using PubMed, Embase, and Google Scholar up to 31 December 2025 according to PRISMA. Case–control studies comparing ERβ expression in CRC biopsy specimens with that in healthy controls were included. A meta-analysis was performed using Comprehensive Meta-analysis (Version 4). Pooled ORs and 95% confidence intervals were calculated using a random-effects model. Heterogeneity was assessed using the Cochrane Q test and the I² statistic. Publication bias was evaluated. Results: Six studies, representing 13 sub-studies, were selected according to the inclusion criteria, involving 1183 patients and 1000 normal mucosa/tumor early-stage patients. The OR for ERβ expression was 0.211 (95%CI: 0.122–0.363), significantly lower in advanced tumor stages than in normal mucosa and early tumor stages (p < 0.0001). Positivity rates were 76.40% in controls and early-stage tumor patients versus 51.31% in tumor patients (all stages). Heterogeneity was high (I² = 78%), but sensitivity analysis confirmed the robustness of the results. Publication bias was not significant. The studies used different methods and positivity cut-off values, with high heterogeneity, and were from only five countries, indicating the possibility of variation in results across other geographical areas or ethnic groups. Conclusions: ERβ expression is significantly lower in CRC tissues than in healthy controls and progressively decreases as the disease progresses. This finding underscores ERβ’s potential role as a prognostic factor and highlights the viability of ERβ activation as a novel therapeutic strategy. Full article

Following the establishment of the four molecular subtypes of breast cancer, additional biomarkers are required to further refine prognostication and patient stratification. Krüppel-like factors (KLFs), components of Wnt signaling, estrogen receptor beta (ERβ) isoforms, cyclin D1, and E-cadherin have been implicated in epithelial–mesenchymal transition, tumor proliferation, and disease progression. In this monocentric retrospective cohort study, tissue microarrays from 153 patients with histologically confirmed breast cancer were analyzed by immunohistochemistry to assess the expression of cytoplasmic Dkk1, β-catenin, and E-cadherin, as well as nuclear cyclin D1, KLF-4, KLF-5, and ERβ isoforms, using the Remmele and Stegner immunoreactive score. Associations between protein expression patterns with clinicopathological characteristics and survival outcomes using univariable and multivariable Cox regression analyses were examined. High cytoplasmic E-cadherin expression was associated with improved overall survival [hazard ratio (HR) 0.37, 95% confidence interval (95% CI) 0.18–0.77, p = 0.008], whereas high nuclear expression of KLF-4 (HR 2.63, 95% CI 1.32–5.22, p = 0.006) and KLF-5 (HR 2.16, 95% CI 1.01–4.65, p = 0.048) was associated with reduced overall survival. High ERβ1 expression showed a marginally protective association with the development of metastases (log-rank test p = 0.045). Importantly, nuclear KLF-4 expression remained independently associated with adverse overall survival after adjustment for tumor stage, lymph node status, molecular subtype, and other molecular markers (adjusted HR 4.09, 95% CI 1.93–8.67, p < 0.001). These findings identify nuclear KLF-4 as an adverse prognostic marker in breast cancer and support its potential relevance for molecular patient stratification. Full article

Although estrogen signaling plays an important role in gynecological cancers, its function is highly context-dependent and often contradictory. Estrogen receptors have been associated with both tumor-promoting and tumor-suppressive effects depending on the tumor type, disease stage, and cellular environment. This review summarizes the current evidence on estrogen receptor signaling in cervical, ovarian, and endometrial cancers, focusing on receptor subtype balance, isoform diversity, cellular and subcellular localization, and epigenetic regulation. Rather than a static marker, estrogen receptor expression is revealed as a dynamic and plastic signaling network. In cervical cancer, estrogen signaling persists despite the loss of epithelial estrogen receptor α (ERα) through stromal signaling, alternative ERα isoforms, ERβ, and non-classical receptors such as G protein-coupled estrogen receptor 1 (GPER1). In ovarian cancer, epigenetic silencing of ERβ and ERα predominance drives oncogenic signaling while also creating specific biological vulnerabilities. In endometrial cancer, estrogen signaling shifts from hormone-dependent initiation to progressive oncogenic autonomy through receptor rewiring and non-genomic pathways. By integrating these mechanisms, this review highlights estrogen receptor plasticity as a unifying concept across gynecological malignancies and outlines key knowledge gaps that are relevant for future endocrine strategies. 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

Despite continuous advances in the development of methodologies for the diagnosis and therapeutic treatment of cancer, the disease remains a primary cause of mortality worldwide. A comprehensive understanding of the molecular mechanisms underlying cancer could ultimately lead to increasingly effective therapeutic interventions. One approach that could be adopted is to formulate methodologies that impede cell signalling and/or the expression of genes pivotal to carcinogenesis. A notable example of this strategy is the focus on the estrogen receptor, a key player in the development of various types of cancer. The deregulation of this receptor, and the subsequent impact on cell function, is a critical factor in the progression of these diseases. This renders it a significant therapeutic target. Furthermore, the microenvironment has been demonstrated to exert a significant influence on the development of cancers. A mounting body of evidence indicates that the abnormal physical properties of the tumour microenvironment can induce widespread changes, leading to the selection of characteristic tumour cell abilities and subsequent clonal proliferation. This process is accompanied by an increased capacity for invasive growth and, notably, the induction of multidrug resistance. The present article focuses on presenting the structure and role of the estrogen receptor in selected hormone-dependent cancers, its involvement in the formation of the tumor microenvironment, currently used therapeutic methods in the treatment of these cancers, and the challenges associated with them. Each new discovery in the field of cancer biology offers the prospect of developing new potential treatments, including targeted therapies aimed at improving the survival of patients suffering from hormone-dependent malignant tumours. Although the role of the estrogen receptor in their development is well established, further research is required to develop a detailed understanding of how its specific isoforms act in different types of cancer. Full article

Background: Cytochromes P450 (CYPs) are heme-containing oxidoreductase enzymes with mono-oxygenase activity. Human CYPs catalyze the oxidation of a great variety of chemicals, including xenobiotics, steroid hormones, vitamins, bile acids, procarcinogens, and drugs. Findings: In our review article, we discuss recent data evidencing that the same CYP isoform can be involved in both bioactivation and detoxification reactions and convert the same substrate to different products. Conversely, different CYP isoforms can convert the same substrate, xenobiotic or procarcinogen, into either a more or less toxic product. These phenomena depend on the type of catalyzed reaction, substrate, tissue type, and biological species. Since the CYPs involved in bioactivation (CYP3A4, CYP1A1, CYP2D6, and CYP2C8) are primarily expressed in the liver, their metabolites can induce hepatotoxicity and hepatocarcinogenesis. Additionally, we discuss the role of drugs as CYP substrates, inducers, and inhibitors as well as the implication of nuclear receptors, efflux transporters, and drug–drug interactions in anticancer drug resistance. We highlight the molecular mechanisms underlying the development of hormone-sensitive cancers, including breast, ovarian, endometrial, and prostate cancers. Key players in these mechanisms are the 2,3- and 3,4-catechols of estrogens, which are formed by CYP1A1, CYP1A2, and CYP1B1. The catechols can also produce quinones, leading to the formation of toxic protein and DNA adducts that contribute to cancer progression. However, 2-hydroxy- and 4-hydroxy-estrogens and their O-methylated derivatives along with conjugated metabolites play cancer-protective roles. CYP17A1 and CYP11A1, which are involved in the biosynthesis of testosterone precursors, contribute to prostate cancer, whereas conversion of testosterone to 5α-dihydrotestosterone as well as sustained activation and mutation of the androgen receptor are implicated in metastatic castration-resistant prostate cancer (CRPC). CYP enzymatic activities are influenced by CYP gene polymorphisms, although a significant portion of them have no effects. However, CYP polymorphisms can determine poor, intermediate, rapid, and ultrarapid metabolizer genotypes, which can affect cancer and drug susceptibility. Despite limited statistically significant data, associations between CYP polymorphisms and cancer risk, tumor size, and metastatic status among various populations have been demonstrated. Conclusions: The metabolic diversity and dual character of biological effects of CYPs underlie their implications in, preliminarily, hormone-sensitive cancers. Variations in CYP activities and CYP gene polymorphisms are implicated in the interindividual variability in cancer and drug susceptibility. The development of CYP inhibitors provides options for personalized anticancer therapy. Full article

Aberrant estrogen receptor (ERα) signaling mediates detrimental effects of tamoxifen including drug resistance and endometrial hyperplasia. ERα36, an alternative isoform of ERα, contributes to these effects. We have demonstrated that CK2 modulates ERα expression and function in breast cancer (BCa). Here, we assess if CX-4945 (CX), a clinical stage CK2 inhibitor, can disrupt ERα66 and ERα36 signaling in BCa. Using live cell imaging, we assessed the antiproliferative effects of CX in tamoxifen-sensitive and tamoxifen-resistant BCa cells in monolayer and/or spheroid cultures. CX-induced alterations in ERα66 and ERα36 mRNA and protein expression were assessed by RT-PCR and immunoblot. Co-immunoprecipitation was performed to determine the differential interaction of ERα isoforms with HSP90 and CK2 upon CX exposure. CX caused concentration-dependent decreases in proliferation in tamoxifen-sensitive MCF-7 and tamoxifen-resistant MCF-7 Tam1 cells and significantly repressed spheroid growth in 3D models. Additionally, CX caused dramatic decreases in endogenous or exogenously expressed ERα66 and ERα36 protein. Silencing of CK2β, the regulatory subunit of CK2, resulted in destabilization and decreased proliferation, similar to CX. Co-immunoprecipitation demonstrated that ERα66/36 show CK2 dependance for interaction with molecular chaperone HSP90. Our findings show that CK2 functions regulate the protein stability of ERα66 and ERα36 through a mechanism that is dependent on CK2β subunit and HSP90 chaperone function. CX may be a component of a novel therapeutic strategy that targets both tamoxifen-sensitive and tamoxifen-resistant BCa, providing an additional tool to treat ERα-positive BCa. Full article

Studies have evaluated vitamin D₃’s therapeutic potential in estrogen-responsive cancers, with conflicting findings. We have shown that the proliferation of breast cancer cells is regulated by 24R,25-dihydroxyvitamin D₃ (24R,25(OH)₂D₃) depending on estrogen receptor alpha 66 (ERα66) expression, suggesting that this could also be the case for estrogen-sensitive laryngeal cancer cells. Accordingly, we examined levels of ERα isoforms in ERα66-positive UM-SCC-12 and ERα66-negative UM-SCC-11A cells and their response to 24R,25(OH)₂D₃. 24R,25(OH)₂D₃ stimulated proliferation, increased the expression of metastatic markers, and inhibited apoptosis in UM-SCC-12 cells while having the opposite effect in UM-SCC-11A cells. To evaluate if vitamin metabolites could act via autocrine/paracrine mechanisms, we assessed the expression, protein levels, and activity of vitamin D₃ hydroxylases CYP24A1 and CYP27B1. Both cell types expressed both mRNAs; but the levels of the enzymes and their activities were differentially regulated by estrogen. ERα66-negative UM-SCC-11A cells produced more 24,25(OH)₂D₃ than UM-SCC-12 cells, but comparable levels of 1,25(OH)₂D₃ when treated with 25(OH)D₃ These results suggest that the regulation of vitamin D₃ metabolism in laryngeal cancer cells is modulated by ERα66 expression, and support a role for 24R,25(OH)₂D₃ as an autocrine/paracrine regulator of laryngeal cancer. The local metabolism of 25(OH)D₃ should be considered when determining the potential of vitamin D₃ in laryngeal cancer. Full article

The etiopathogenesis of preeclampsia, a leading hypertensive disorder of pregnancy, has been proposed to involve an abnormal circulating sex hormone profile and misexpression of placental estrogen and progesterone receptors (ER and PR, respectively). However, existing research is vastly confined to third trimester preeclamptic placentas. Consequently, the placental–uterine molecular crosstalk and the dynamic ER and PR expression pattern in the peri-conception period remain overlooked. Herein, our goal was to use the BPH/5 mouse to elucidate pre-pregnancy and early gestation Er and Pr dynamics in a preeclamptic-like uterus. BPH/5 females display low circulating estrogen concentration during proestrus, followed by early gestation hypoestrogenemia, hyperprogesteronemia, and a spontaneous preeclamptic-like phenotype. Preceding pregnancy, the gene encoding Er alpha (Erα, Esr1) is upregulated in the diestrual BPH/5 uterus. At the peak of decidualization, Esr1, Er beta (Erβ, Esr2), and Pr isoform B (Pr-B) were upregulated in the BPH/5 maternal–fetal interface. At the protein level, BPH/5 females display higher percentage of decidual cells with nuclear Erα expression, as well as Pr downregulation in the decidua, luminal and glandular epithelium. In conclusion, we provide evidence of disrupted sex hormone signaling in the peri-conception period of preeclamptic-like pregnancies, potentially shedding some light onto the intricate role of sex hormone signaling at unexplored timepoints of human preeclampsia. Full article

Endometrial cancer (EC) is one of the most common types of cancer in Poland and worldwide. Many risk factors lead to the pathogenesis of this disease, such as lifestyle choices, BMI, the medicines used in breast cancer therapy, and Lynch syndrome. EC cells show the expression of estrogen receptors (ERs) and progesterone receptors (PgR). These receptors occur in multiple isoforms and have a significant influence on the operation of cells. The loss of ER and PgR expression is associated with a poor prognosis. We assessed tissue slides that were obtained from 103 women with EC diagnoses of various grades, stages, and histological types. In this study, we used computer image analyses to increase the objectivity of the assessment. We proved that, in the tissue of patients with high-grade (G3) EC, the expression of PgR is significantly lower than that in the tissues of patients with low-grade EC. We also observed that PgR is significantly expressed in EC with a low FIGO stage and in the endometroid type of EC (which rarely becomes malignant compared to serous type). The expression of ERb1 was lower in patients with EC at the IV FIGO stage than in patients with stage III EC. These findings confirm that the loss of ER and PgR expression is connected with a poor prognosis. Full article

Background: Sex-specific differences in heart disease outcomes are influenced by the levels of the steroid hormones, estrogen and testosterone. While the roles of estrogen receptors in cardiac disease are well-studied in animals and humans, respective research on androgen receptors (AR) is limited. Here we investigate AR protein and mRNA expression in human myocardium of various cardiac diseases. Methods: AR expression was analyzed by western blotting in myocardium from human non-failing hearts (NF, n = 6) and patients with aortic stenosis (AS, n = 6), hypertrophic cardiomyopathy (HCM, n = 7), dilated cardiomyopathy (DCM, n = 7), and ischemic cardiomyopathy (ICM, n = 7). Using an AR45-specific antibody, a subsequent western blot assessed samples from male and female patients with HCM (n = 10) and DCM (n = 10). The same sample set was probed for full-length AR and AR45 mRNA expression. Immunohistochemistry (IHC) localized AR in myocardium from HCM and AS hearts. Results: Full-length AR was notably enriched in AS and HCM hearts compared to ICM, DCM, and NF. Similarly, AR45 was more abundant in HCM than in DCM. In contrast to the pattern observed for AR protein, full-length AR mRNA levels were lower in HCM compared to DCM, with no discernible difference for the AR45 isoform. Although gender differences in AR expression were not detected in western blots or qRT-PCR, IHC showed stronger nuclear AR signals in males than in females. Conclusions: Our findings indicate disease-specific regulation of AR mRNA and/or AR protein in cardiac hypertrophy, underscoring a potential role in this cardiac pathology. Full article

Genistein is a natural compound belonging to flavonoids, having antioxidant, anti-inflammatory, and anti-neoplastic properties. Genistein is considered a phytoestrogen. As such, genistein can bind estrogen receptors (ERα and ERβ), although with a lower affinity than that of estradiol. Despite considerable work, the effects of genistein are not well established yet. This review aims to clarify the role of genistein on female and male reproductive functions in mammals. In females, at a high dose, genistein diminishes the ovarian activity regulating several pathway molecules, such as topoisomerase isoform I and II, protein tyrosine kinases (v-src, Mek-4, ABL, PKC, Syk, EGFR, FGFR), ABC, CFTR, Glut1, Glut4, 5α-reductase, PPAR-γ, mitogen-activated protein kinase A, protein histidine kinase, and recently circulating RNA-miRNA. The effect of genistein on pregnancy is still controversial. In males, genistein exerts an estrogenic effect by inducing testosterone biosynthesis. The interaction of genistein with both natural and synthetic endocrine disruptors has a negative effect on testis function. The positive effect of genistein on sperm quality is still in debate. In conclusion, genistein has a potentially beneficial effect on the mechanisms regulating the reproduction of females and males. However, this is dependent on the dose, the species, the route, and the time of administration. Full article

This study investigated the interplay between transforming growth factor beta (TGF-β1/T1 and TGF-β3/T3), and sex hormone receptors using our 3D in vitro cornea stroma model. Primary human corneal fibroblasts (HCFs) from healthy donors were plated in transwells at 10⁶ cells/well and cultured for four weeks. HCFs were supplemented with stable vitamin C (VitC) and stimulated with T1 or T3. 3D construct proteins were analyzed for the androgen receptor (AR), progesterone receptor (PR), estrogen receptor alpha (ERα) and beta (ERβ), luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), gonadotropin-releasing hormone receptor (GnRHR), KiSS1-derived peptide receptor (KiSS1R/GPR54), and follicle-stimulating hormone subunit beta (FSH-B). In female constructs, T1 significantly upregulated AR, PR, ERα, FSHR, GnRHR, and KiSS1R. In male constructs, T1 significantly downregulated FSHR and FSH-B and significantly upregulated ERα, ERβ, and GnRHR. T3 caused significant upregulation in expressions PR, ERα, ERβ, LHR, FSHR, and GNRHR in female constructs, and significant downregulation of AR, ERα, and FSHR in male constructs. Semi-quantitative Western blot findings present the interplay between sex hormone receptors and TGF-β isoforms in the corneal stroma, which is influenced by sex as a biological variable (SABV). Additional studies are warranted to fully delineate their interactions and signaling mechanisms. Full article

Estrogen receptor beta 1 (ERβ1) is a ligand-activated nuclear receptor, which has been shown to maintain tissue differentiation in the normal prostate, and regulate androgen response and increase expression of tumor suppressors in prostate cancer cell lines. There are three shorter isoforms of ERβ expressed in the human prostate, ERβ2, ERβ4, and ERβ5, which have already been implicated in chemotherapy resistance and disease progression, suggesting a possible oncogenic role. Their ligand-binding domain (LBD) is truncated, so they are unable to activate canonical ERβ1 signaling pathways; however, they were shown to participate in hypoxic signaling and to induce a gene expression signature associated with stemness and hypoxia. To elucidate the role of the truncated ERβ isoforms in prostate cancer, we created a knockout of all isoforms, as well as a truncation of the LBD, to remove the function of ERβ1. We showed that the removal of all isoforms leads to a decrease in the expression of cancer stem cell (CSC)-associated genes, decreased chemotherapy resistance, and a decrease in the CSC population, based on sphere formation ability and SORE6 (CSC reporter) activity, while removing the LBD function only had the opposite effect. Our results suggest a more aggressive phenotype in prostate cancer cell lines expressing ERβ variants. Full article

Current advances in molecular profiling methodologies and the accessibility of multi-omics datasets are paving the way toward a better understanding of heterogeneous diseases, including breast cancer (BC). In this regard, we sought to uncover the transcriptional changes triggered by estrogen and insulin in a primary BC cell line (BCAHC-1), which expresses the 46kDa isoform of the estrogen receptor (ER)α and the insulin receptor, as we have previously ascertained. Raw data from RNA sequencing of BCAHC-1 cells were processed by the Bcl2Fastq 2.20 version of the Illumina pipeline, while in silico analyses were performed in R Studio using the TCGA dataset. Real-time PCR, immunoblotting, ELISA and chromatin immunoprecipitation experiments were used to identify the molecular events triggered by estrogen and insulin in BCAHC-1 cells and cancer-associated fibroblasts (CAFs). Furthermore, migration and invasion assays allowed us to ascertain the mechanisms triggering these biological responses in the presence of the aforementioned hormone treatments. First, we determined that 17β-estradiol (E2) and insulin stimulate a peculiar IL-11 expression and IL-11 secretion in BCAHC-1 cells. Thereafter, bioinformatics analyses confirmed the up-regulation of IL-11 in ER-positive BCs, with respect to adjacent normal tissues, and its association with worse survival. Next, the involvement of IL-11 in pro-metastatic transduction signaling was established via pathway enrichment analyses. Notably, we found that the secretion of IL-11 by BCAHC-1 cells prompts an invasive phenotype of CAFs through the up-regulation of genes belonging to the extracellular matrix organization pathway, namely, the intercellular adhesion molecule 1 and integrin alpha 5. Overall, our findings indicate that IL-11 secretion by BC cells may elicit a paracrine action on the surrounding stroma and introduce invasive properties, suggesting that IL-11 could be considered a valuable target in comprehensive treatments of ER-positive BC patients. Full article