Effects Of Estrogen Receptor Research Articles

Profiling the endocrine disrupting properties of triazines, triazoles and short-chain PFAS.

Persistent, mobile and toxic (PMT) compounds released to the environment are likely to pollute drinking water sources due to their slow environmental degradation (persistency) and high water solubility (mobility). The aim of the present study was to create in vitro hazard profiles for sixteen triazoles, nine triazines and eleven PFAS based on their agonistic and antagonistic effects in estrogen receptor (ER), androgen receptor (AR) and thyroid hormone receptor (TR) reporter gene assays, their ability to bind human transthyretin (TTR), and their effects on steroidogenesis. The triazole fungicides tetraconazole, bitertanol, fenbuconazole, tebuconazole, cyproconazole, difenoconazole, propiconazole, paclobutrazol and triadimenol had agonistic or antagonistic effects on the ER and AR. Difenoconazole, propiconazole and triadimenol were also found to be TR antagonists. The triazine herbicide ametryn was an ER, AR and TR antagonist. The same nine triazole fungicides and the triazines atrazine, deethyl-atrazine and ametryn affected the secretion of steroid hormones. Furthermore, PFAS compounds PFBS, PFHxS, PFHxA, PFOS, PFOA and GenX and the triazoles bitertanol, difenoconazole and 4-methyl benzotriazole were found to displace T4 from TTR. These results are in line with earlier in vitro and in vivo studies on the endocrine disrupting properties of triazines, triazoles and PFAS. The present study demonstrates that this battery of in vitro bioassays can be used to profile compounds from different classes based on their endocrine disrupting properties as a first step to prioritize them for further research, emission reduction, environmental remediation and regulatory purposes.

Effect of estrogen receptor α on cardiopulmonary adaptation to chronic developmental hypoxia in a rat model.

Humans living at high-altitude (HA) have adapted to this environment by increasing pulmonary vascular and alveolar growth. RNA sequencing data from a novel murine model that mimics this phenotypical response to HA suggested estrogen signaling via estrogen receptor alpha (ERα) may be involved in this adaptation. We hypothesized ERα was a key mediator in the cardiopulmonary adaptation to chronic hypoxia and sought to delineate the mechanistic role ERα contributes to this process by exposing novel loss-of-function ERα mutant (ERαMut) rats to simulated HA. ERα mutant or wild-type (wt) rats were exposed to normoxia or hypoxia starting at conception and continued postnatally until 6 wk of age. Both wt and ERαMut animals born and raised in hypoxia exhibited lower body mass and higher hematocrits, total alveolar volumes (Va), diffusion capacities of carbon monoxide (DLCO), pulmonary arteriole (PA) wall thickness, and Fulton indices than normoxia animals. Right ventricle adaptation was maintained in the setting of hypoxia. Although no major physiologic differences were seen between wt and ERαMut animals at either exposure, ERαMut animals exhibited smaller mean linear intercepts (MLI) and increased PA total and lumen areas. Hypoxia exposure or ERα loss-of-function did not affect lung mRNA abundance of vascular endothelial growth factor, angiopoietin 2, or apelin. Sexual dimorphisms were noted in PA wall thickness and PA lumen area in ERαMut rats. In summary, in room air-exposed rats and rats with peri- and postnatal hypoxia exposure, ERα loss-of-function was associated with decreased alveolar size (primarily driven by hypoxic animals) and increased PA remodeling.NEW & NOTEWORTHY By exposing novel loss-of-function estrogen receptor alpha (Erα) mutant rats to a novel model of human high-altitude exposure, we demonstrate that ERα has subtle but inconsistent effects on endpoints relevant to cardiopulmonary adaptation to chronic hypoxia. Given that we observed some histologic, sex, and genotype differences, further research into cell-specific effects of ERα during hypoxia-induced cardiopulmonary adaptation is warranted.

Effect of Estrogen Receptor on the Relationship Between HER2 Immunohistochemistry Score and Pathological Complete Response to Neoadjuvant Treatment in HER2‐Positive Breast Cancer

Effect of Estrogen Receptor on the Relationship Between HER2 Immunohistochemistry Score and Pathological Complete Response to Neoadjuvant Treatment in HER2‐Positive Breast Cancer

Association of Estrogen Receptors with Polycystic Ovary Syndrome and Subsequent Infertility in Affected Patients

Background: Polycystic ovarian syndrome (PCOS) is the reproductive and metabolic abnormality of females characterized by delayed folliculogenesis, hyperandrogenism, and multiple ovarian cysts, associated with an increased risk of infertility, abortion and endometrial cancer. Objectives: Therefore, the effects of estrogen receptors on PCOS incidence were investigated through quantification of ER-α and ER-β mRNAs expressions via RT-PCR. Study Design: This cross-sectional study was executed at Mayo Hospital Lahore, from January-2021 to September-2022, including 320 participants. Methods: 180 females enrolled in this study were diagnosed with PCOS. ER-α and ER-β were isolated and amplified separately on RT-PCR for their quantification. Results: It was found that expression of tER-α mRNA did not differ between size-matched normal and PCOS follicles, and the concentration of both types of nitrogenous bases, GC and TC, was equivalent. Yet, ER-β mRNA expression was substantially higher in TC (p<0.05) than in GC. Conclusion: It was concluded that PCOS is the major cause of infertility among Pakistani women. It is mostly curable if identified accurately. Established on ER and haplotype data, genetic coding for ER-α and ER-β mRNA are good markers for determination of the association of estrogen receptors with PCOS. Keywords: Endocrine disorder; Estrogen receptors; Genetic coding; Infertility.

Pharmacological Targeting of Androgen Receptor Elicits Context-Specific Effects in Estrogen Receptor-Positive Breast Cancer.

The ratio of androgen receptor to estrogen receptor in breast cancer dictates the response to AR-targeted therapies, providing guidelines for developing AR-directed treatment strategies for patients with breast cancer.

P53 Mutation as Plausible Predictor for Endocrine Resistance Therapy in Luminal Breast Cancer.

Endocrine therapy resistance in Luminal Breast Cancer is a significant issue to be tackled, but currently, no specific biomarker could be used to anticipate this event. p53 mutation is widely known as one of Breast Cancer's most prominent genetic alterations. Its mutation could generate various effects in Estrogen Receptor and Progesterone Receptor molecular works, tangled in events leading to the aggravation of endocrine therapy resistance. Hence the possibility of p53 mutation utilization as an endocrine therapy resistance predictive biomarker is plausible. The purpose of this review is to explore the latest knowledge of p53 role in Estrogen Receptor and Progesterone Receptor molecular actions, thus aggravating the Endocrine Therapy resistance in Luminal Breast Cancer, from which we could define possibilities and limitations to utilize p53 as the predictive biomarker of endocrine therapy resistance in Luminal Breast Cancer.

Impact of estrogen receptor expression on prognosis of ovarian cancer according to antibody clone used for immunohistochemistry: a meta-analysis

BackgroundThe prognostic value of the expression of estrogen receptor (ER) subtypes ER⍺ and ERβ in ovarian cancer has previously been evaluated by meta-analyses. However, the results are contradictory and controversial.MethodsWe conducted an updated meta-analysis with stringent inclusion criteria to ensure homogeneous studies to determine the effect of ER subtypes on ovarian cancer prognosis. Articles were retrieved by systematic search of PubMed and Web of Science for articles dated up to June 2021. Only studies with known hazard ratio (HR) and antibody clone for immunochemistry (IHC) were included. Pooled HRs with the corresponding 95% confidence intervals (CIs) were calculated for the effect of ER⍺ and ERβ expression on ovarian cancer patient progression-free survival (PFS) and overall survival (OS).ResultsA total of 17 studies were included, of which 11 and 13 studies examined the relationships between ER⍺ expression and PFS and OS, respectively, and 5 and 7 studies examined the relationships between ERβ expression and PFS and OS, respectively. Neither ER⍺ expression (random-effects model; HR = 0.99, 95% CI = 0.83–1.18) nor ERβ expression (fixed-effects model; HR = 0.94, 95% CI = 0.69–1.27) was associated with PFS. Random-effects models showed that ER⍺ expression (HR = 0.81, 95% CI = 0.64–1.02) and ERβ expression (HR = 0.75, 95% CI = 0.50–1.13) were only marginally and not significantly associated with better OS. Subgroup analysis revealed that ER⍺ expression determined using antibody clone 1D5 (HR = 0.75, 95% CI = 0.64–0.88) and ERβ expression determined using ERβ1-specific-antibody clone PPG5/10 or EMR02 (HR = 0.65, 95% CI = 0.50–0.86) were associated with significantly better OS, but ER expression determined using other antibodies was not.ConclusionsIn conclusion, a higher ER⍺ expression and ERβ expression are significantly associated with a better survival of ovarian cancer patients, but the results from previous prognostic studies are significantly dependent on the choice of specific ER antibody clones used in immunohistochemistry analysis.

Selective estrogen receptor α and β antagonist aggravate cardiovascular dysfunction in type 2 diabetic ovariectomized female rats.

Type 2 diabetes (T2D) is a major risk factor for cardiovascular disorders (CVD), characterized by pathological diastolic as well as systolic dysfunction, ventricular dilation, and cardiomyocyte hypertrophy. CVD is the main cause of death in postmenopausal women. Estradiol (E2) has protective effects on cardiovascular function. The biological effects of E2 are mainly mediated by classical estrogen receptors (ERs). The present study aimed to investigate the cardioprotective effects of classical ERs in ovariectomized (OVX) diabetic female rats. T2D was induced in female rats by high-fat diet feeding along with a low dose of streptozotocin. Then diabetic animals were divided into eight groups: Sham-control, OVX, OVX+Vehicle (Veh), OVX+E2, OVX+E2+MPP (ERα antagonist), OVX+E2+PHTPP (ERβ antagonist), OVX+E2+Veh, OVX+E2+MPP+PHTPP. Animals received E2, MPP, and PHTPP every four days for 28days. At the end blood was collected, serum separated, and used for biochemical parameters. Heart tissue was used for cardiac angiotensin II and cytokines measurement. E2 treatment improved the metabolic disorders caused by T2D, and its receptor antagonists intensified the effects of T2D on the metabolic status. Also, E2 therapy decreased cardiac inflammatory cytokines, and MPP and PHTPP increased cardiac inflammation by increasing TNF-α and IL-6 and decreasing IL-10. Classical ERs have protective effects on diabetic hearts by improving the metabolic status and inflammatory balance.

P53 Mutation as Plausible Predictor for Endocrine Resistance Therapy in Luminal Breast Cancer.

Endocrine therapy resistance in Luminal Breast Cancer is a significant issue to be tackled, but currently no specific biomarker could be used to anticipate this event. p53 mutation is widely known as one of Breast Cancer's most prominent genetic alterations. Its mutation could generate various effects in Estrogen Receptor and Progesteron Receptor molecular works, tangled in events leading to the aggravation of endocrine therapy resistance. Hence the possibility of p53 mutation utilization as an endocrine therapy resistance predictive biomarker is plausible. The purpose of this review is to explore the latest knowledge of p53 role in Estrogen Receptor and Progesteron Receptor molecular actions thus aggravating the Endocrine Therapy resistance in Luminal Breast Cancer, from which we could define possibilities and limitations to utilize p53 as the predictive biomarker of endocrine therapy resistance in Luminal Breast Cancer.

Distribution and Effects of Estrogen Receptors in Prostate Cancer: Associated Molecular Mechanisms.

Estrogens are hormones that have been extensively presented in many types of cancer such as breast, uterus, colorectal, prostate, and others, due to dynamically integrated signaling cascades that coordinate cellular growth, differentiation, and death which can be potentially new therapeutic targets. Despite the historical use of estrogens in the pathogenesis of prostate cancer (PCa), their biological effect is not well known, nor their role in carcinogenesis or the mechanisms used to carry their therapeutic effects of neoplastic in prostate transformation. The expression and regulation of the estrogen receptors (ERs) ERα, ERβ, and GPER stimulated by agonists and antagonists, and related to prostate cancer cells are herein reviewed. Subsequently, the structures of the ERs and their splice variants, the binding of ligands to ERs, and the effect on PCa are provided. Finally, we also assessed the contribution of molecular simulation which can help us to search and predict potential estrogenic activities.

The Effects of Estrogen Receptor β or G Protein-Coupled Receptor 30 Activation on Anxiety-Liked Behaviors in Relation to GABAergic Transmission in Stress-Ovariectomized Rats

The Effects of Estrogen Receptor β or G Protein-Coupled Receptor 30 Activation on Anxiety-Liked Behaviors in Relation to GABAergic Transmission in Stress-Ovariectomized Rats

Treatment Strategies Against Triple-Negative Breast Cancer: An Updated Review.

Triple-negative breast cancer (TNBC) is associated with an increased risk of early recurrence and distant metastasis, as well as the development of therapeutic resistance and poor prognosis. TNBC is characterized by a wide range of genetic, immunophenotypic, morphological, and clinical features. TNBC is coined to describe cancers that lack estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). As a result, hormonal or trastuzumab-based treatments are ineffective in TNBC patients. TNBCs are biologically aggressive, and despite some evidence that they respond to treatment better than other forms of breast cancer, the prognosis remains poor. This is attributed to a shorter disease-free interval in adjuvant and neoadjuvant settings, as well as a more aggressive metastatic course. TNBC has a lot of clinical ramifications. In terms of new treatment methods, TNBC has lagged behind other types of breast cancer. There are not many options for treating this form of breast cancer because it is progressive. Many effective treatments for most breast cancers block the growth-stimulating effects of ER, PR, and/or HER2, leaving TNBC with few choices. Finding new and effective treatment options for TNBC remains a critical clinical need. To develop more effective drugs, new experimental approaches must be tested in patients with TNBC.

Understanding the Role of Estrogen Receptor Status in PRODH/POX-Dependent Apoptosis/Survival in Breast Cancer Cells.

Simple SummaryThe estrogen receptor (ER) status and the availability of agonists or antagonists of these receptors determine the processes of growth, differentiation, and proliferation of breast cancer cells. Estrogens and anti-estrogenic compounds have been shown to influence breast cancer cell survival/apoptosis via action through the mitochondrial enzyme proline dehydrogenase/proline oxidase (PRODH/POX). In this review, we highlight the molecular effects of ER stimulation/inhibition in signaling pathways.It has been suggested that activation of estrogen receptor α (ER α) stimulates cell proliferation. In contrast, estrogen receptor β (ER β) has anti-proliferative and pro-apoptotic activity. Although the role of estrogens in estrogen receptor-positive breast cancer progression has been well established, the mechanism of their effect on apoptosis is not fully understood. It has been considered that ER status of breast cancer cells and estrogen availability might determine proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that converts proline into pyrroline-5-carboxylate (P5C). During this process, ATP (adenosine triphosphate) or ROS (reactive oxygen species) are produced, facilitating cell survival or death, respectively. However, the critical factor in driving PRODH/POX-dependent functions is proline availability. The amount of this amino acid is regulated at the level of prolidase (proline releasing enzyme), collagen biosynthesis (proline utilizing process), and glutamine, glutamate, α-ketoglutarate, and ornithine metabolism. Estrogens were found to upregulate prolidase activity and collagen biosynthesis. It seems that in estrogen receptor-positive breast cancer cells, prolidase supports proline for collagen biosynthesis, limiting its availability for PRODH/POX-dependent apoptosis. Moreover, lack of free proline (known to upregulate the transcriptional activity of hypoxia-inducible factor 1, HIF-1) contributes to downregulation of HIF-1-dependent pro-survival activity. The complex regulatory mechanism also involves PRODH/POX expression and activity. It is induced transcriptionally by p53 and post-transcriptionally by AMPK (AMP-activated protein kinase), which is regulated by ERs. The review also discusses the role of interconversion of proline/glutamate/ornithine in supporting proline to PRODH/POX-dependent functions. The data suggest that PRODH/POX-induced apoptosis is dependent on ER status in breast cancer cells.

Abstract 876: TP53 pathway function, estrogen receptor status, and breast cancer risk factors in the Carolina Breast Cancer Study

Abstract Purpose: TP53 and estrogen receptor (ER) both play essential roles in breast cancer development and progression, with recent research revealing crosstalk between TP53 and ER signaling pathways. While many studies have demonstrated heterogeneity of risk factor associations across ER subtypes, TP53 status has been inconsistently linked to breast cancer risk factors. This may be due to few studies evaluating TP53 effects in the context of ER. Additionally, studies have generally classified TP53 status using immunohistochemistry (IHC) staining or DNA sequencing, which are prone to misclassification of TP53 pathway function. RNA-based methods of measuring TP53 pathway activity may reduce misclassification and clarify etiologic associations. Methods: This case-only analysis included 4,466 incident breast cancer cases from the Carolina Breast Cancer Study (1993-2013). Using RNA expression previously quantified using NanoString assays on FFPE tumor samples, tumors were classified for TP53 functional status (mutant-like or wildtype-like) using a validated 52-gene RNA signature. We used a two-stage polytomous logistic regression model to evaluate sources of risk factor heterogeneity due to RNA-based TP53 or ER, adjusting for each other and for PR, HER2, and grade, while accounting for missing tumor marker data. Risk factor heterogeneity was also evaluated for IHC-based TP53 and ER. For each risk factor, joint effects of TP53 and ER were evaluated by allowing for an interaction between the two markers. Results: When classifying TP53 status using the RNA signature, the effects of several hormone-related factors (oral contraceptive use, menopausal status, age at menopause, and pre- and post-menopausal BMI) were heterogeneous across TP53 subtypes, while heterogeneity of reproductive factors (age at first birth and parity) and smoking status was observed across ER subtypes. The effect of number of births was heterogenous across both TP53 and ER-based subtype definitions. Additionally, we observed an interaction between RNA-based TP53 and ER status with family history of breast cancer in a first-degree relative (p=0.05). When classifying TP53 status using IHC, the TP53 effects were not recapitulated but there was minimal change in the ER effects. We observed an interaction between IHC-based TP53 and ER status with age at menarche (p=0.02), smoking status (p=0.05), and alcohol use (p=0.06). Conclusions: This study demonstrates that TP53 and ER are valuable for defining etiologic subtypes of breast cancer, although IHC measures may not have as much value as RNA. Analyses of the joint effects of TP53 and ER with breast cancer risk factors revealed intriguing findings that could lead to new hypotheses. However, larger studies incorporating multiple correlated tumor characteristics will be required to confirm our findings to conclusively define etiologically relevant subtypes of breast cancer. Citation Format: Amber N. Hurson, Mustapha Abubakar, Kathleen Conway-Dorsey, Katherine Hoadley, Michael I. Love, Andrew F. Olshan, Montserrat Garcia-Closas, Melissa A. Troester. TP53 pathway function, estrogen receptor status, and breast cancer risk factors in the Carolina Breast Cancer Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 876.

Region-specific effects of blocking estrogen receptors on longitudinal bone growth.

Estrogen receptors (ERs) regulate the development of the growth plate (GP) by binding to estrogen, a phenomenon that determines the growth of skeletal bone. However, the exact mechanisms underlying the regulatory effects of ERs on axial and appendicular growth plates during puberty remain unclear. In the present study, the strategy of ERβ blocking resulted in increased longitudinal elongation of the appendicular bone (P < 0.01), whereas ERα blocking suppressed appendicular elongation (P < 0.05). Blocking both ERs did not have opposite effects on axial longitudinal growth. The expression of chondrocyte proliferation genes including collagen II, aggrecan, and Sox9 and hypertrophic marker genes including collagen X, MMP13, and Runx2 was significantly increased in the growth plate of female mice treated with ERβ antagonist compared with that in the GP of control mice (P < 0.05). There were no significant differences in local insulin-like growth factor 1 (IGF-1) expression among these groups (P > 0.05), and Indian hedgehog protein (Ihh) and parathyroid-related protein (PTHrP) expressions differed among these groups (P < 0.05). ERs appeared not to affect axial bone growth during puberty in female mice (P > 0.05). Our data show that the blocking of different ER subtypes might have a region-specific influence on longitudinal appendicular and axial growth.

Selective ER-β agonists alleviate neuronal deficits in insulin-resistant estrogen-deficient rats

Objective The present study aimed to determine the effect of estrogen receptor (ER) agonists on depression and memory impairment in insulin-resistant ovariectomized (OVX) rats. Methods Rats underwent bilateral ovariectomy, and low-dose streptozotocin (STZ) and a high-fat diet (58% fat, 25% protein, and 17% carbohydrates as a percentage of kilocalories) were administered to induce an estrogen-deficient insulin-resistant state. After 1 week of STZ administration, rats were treated with 17β-estradiol (17βE2) and selective ER-α (propylpyrazoletriol) and ER-β (diarylpropionitrile) agonists (10 μg/kg subcutaneously). Memory was evaluated using the Morris water maze and depression using the forced swim test. Results Treatment with selective ER-β agonist and 17βE2 but not with selective ER-α agonist significantly modulated the neurobehavioral deficits in insulin-resistant OVX rats. These neurobehavioral parameters were further correlated with brain-derived neurotrophic factor (BDNF) levels and acetylcholinesterase (AChE) activity. Selective ER-β agonist and 17βE2 significantly modulated BDNF levels and AChE activity in insulin-resistant OVX rats. Significant increases in estradiol and uterine weight were observed in 17βE2-treated rats, but selective ER agonists did not show any effect. Conclusion ER-β agonist can be an effective strategy for the mitigation of memory loss and depression in an estrogen-deficient insulin-resistant state without all of the deleterious feminizing effects that occur with the use of 17βE2.

16α-hydroxyestrone and its receptor complex: high affinity antigen for antibodies from prostate cancer patients

Background and objectives: Elevated levels of 16α-hydroxyestrone (16α-OHE1) have been linked to increased risk of prostate cancer (PC) and estrogen receptor (ER) had been expressed in prostate tissue but the combined effect of 16α-OHE1 and ER (α) is lacking. We investigated the binding specificity of antibodies from PC with 16α-OHE1-ER complex in the sera from PC patients. Materials and methods: The antibodies in the serum from 60 PC patients and 40 control subjects were evaluated from ELISA (direct binding and competition) and quantitative precipitin titration. Competition ELISA was also used to estimates 16α-OHE1 concentration and 2-hydroxyestrone (2-OHE1)/16α-OHE1 ratio in PC patients. Results: Antibodies from PC patients demonstrate high binding to 16α-OHE1-ER in comparison to ER (p &lt; 0.05) or 16α-OHE1 (p &lt; 0.001). The relative affinity of PC IgG was found to be high for 16α-OHE1-ER (1.19 × 10−7 M) as compared to ER (1.45 × 10−6 M) or 16α-OHE1 (1.13 × 10−6 M). Conclusion: High affinity of PC IgG with 16α-OHE1-ER might explain the possible antigenic role and 16α-OHE1-ER acted as high affinity antigen for antibodies from PC. The interaction between 16α-OHE1 and ER makes a complex in the prostate tissues and this may generate antibodies against this complex in the cancer patients.

Cyclic depsipeptide mycotoxin exposure may cause human endocrine disruption: Evidence from OECD in vitro stably transfected transcriptional activation assays

The presence of cyclic depsipeptide mycotoxins in foods and feedstuffs could potentially cause endocrine disrupting effects on humans and wildlife by their inhibition of active steroidogenesis. Therefore, we attempted to assess the human estrogen receptor (ER) and androgen receptor (AR) agonistic/antagonistic effects of representative cyclic depsipeptide mycotoxins, enniatin A1 (ENN A1), and enniatin B1 (ENN B1), by OECD Performand Based Test Guideline (PBTG) No.455, VM7Luc ER transcriptional activation (TA) assay and OECD TG No. 458, 22Rv1/MMTV_GR-KO AR TA assay. No tested cyclic depsipeptide mycotoxins were found to be ER and AR agonists in VM7Luc ER TA and 22Rv1/MMTV_GR-KO AR TA assays. On the other hand, ENN A1, and ENN B1 exhibited the ER and AR antagonistic effects with IC30 and IC50 values in both TA assays. These two cyclic depsipeptide mycotoxins, which were determined as ER and AR antagonists by two in vitro assays, bound to ERα, and AR. Then ENN A1, and ENN B1 inhibited the dimerization of ERα, and AR. These results, for the first time indicated that ENN A1, and ENN B1 could have potential endocrine disrupting effects mediated by interaction of ERα and AR using international standard testing methods to determine the potential endocrine disrupting chemical.

Effects of Estrogen Receptor and Wnt Signaling Activation on Mechanically Induced Bone Formation in a Mouse Model of Postmenopausal Bone Loss.

In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated manner. Because the response of bone to mechanical signals is dependent on functional estrogen receptor (ER) and Wnt/β-catenin signaling and is impaired in postmenopausal osteoporosis by estrogen deficiency, it is of paramount importance to elucidate the underlying mechanisms as a basis for the development of new strategies in the treatment of osteoporosis. The present study aimed to investigate the effectiveness of the activation of the ligand-dependent ER and the Wnt/β-catenin signal transduction pathways on mechanically induced bone formation using ovariectomized mice as a model of postmenopausal bone loss. We demonstrated that both pathways interact in the regulation of bone mass adaption in response to mechanical loading and that the activation of Wnt/β-catenin signaling considerably increased mechanically induced bone formation, whereas the effects of estrogen treatment strictly depended on the estrogen status in the mice.

Protein disulfide isomerase A1 regulates breast cancer cell immunorecognition in a manner dependent on redox state.

Oxidoreductase protein disulphide isomerases (PDI) are involved in the regulation of a variety of biological processes including the modulation of endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER-mitochondria communication and the balance between pro-survival and pro-death pathways. In the current study the role of the PDIA1 family member in breast carcinogenesis was investigated by measuring ROS generation, mitochondrial membrane disruption, ATP production and HLA-G protein levels on the surface of the cellular membrane in the presence or absence of PDIA1. The results showed that this enzyme exerted pro-apoptotic effects in estrogen receptor (ERα)-positive breast cancer MCF-7 and pro-survival in triple negative breast cancer (TNBC) MDA-MB-231 cells. ATP generation was upregulated in PDIA1-silenced MCF-7 cells and downregulated in PDIA1-silenced MDA-MB-231 cells in a manner dependent on the cellular redox status. Furthermore, MCF-7 and MDA-MB-231 cells in the presence of PDIA1 expressed higher surface levels of the non-classical human leukocyte antigen (HLA-G) under oxidative stress conditions. Evaluation of the METABRIC datasets showed that low PDIA1 and high HLA-G mRNA expression levels correlated with longer survival in both ERα-positive and ERα-negative stage 2 breast cancer patients. In addition, analysis of the PDIA1 vs. the HLA-G mRNA ratio in the subgroup of the living stage 2 breast cancer patients exhibiting low PDIA1 and high HLA-G mRNA levels revealed that the longer the survival time of the ratio was high PDIA1 and low HLA-G mRNA and occurred predominantly in ERα-positive breast cancer patients whereas in the same subgroup of the ERα-negative breast cancer mainly this ratio was low PDIA1 and high HLA-G mRNA. Taken together these results provide evidence supporting the view that PDIA1 is linked to several hallmarks of breast cancer pathways including the process of antigen processing and presentation and tumor immunorecognition.