Estrogen Receptor Expression Research Articles

Effect of Different Concentrations of PRP on the Expression of Factors Involved in the Endometrial Receptivity in the Human Endometrial Cells from RIF Patients Compared to the Controls.

Platelet-rich plasma (PRP) has been suggested for the improvement of endometrial growth and receptivity in the patients with recurrent implantation failure (RIF). The aim of present study was to investigate the impact of different concentration of PRP on the expression of genes involved in the endometrial receptivity in the human endometrial cells from RIF and controls with thin and normal endometrium in vitro. In this cross-sectional study, endometrial biopsies were obtained from 14 healthy fertile women and 14 women with RIF. Endometrial cells from 4 different group (RIF and control with endometrial thickness < 7mm and > 7mm) were cultured with three different concentration of PRP 3%, 5% and 10%. Expression of leukemia inhibitory factor (LIF), COX2 and P53, estrogen receptors (ERs) and progesterone receptors (PRs) genes were measured using quantitative real-time polymerase chain reaction (PCR). Protein expression levels of LIF, COX2 and p53 were evaluated using Western Blot method (WB). There was a significant decrease in the expression of PROA/b, ER2/b, LIF/b, COX2/b and P53/b genes in the RIF groups compared to the controls. Treatment with 5% and 10% PRP caused a significant increase in the gene expression of PRs, ERs, LIF/b, COX2/b and p53 in the RIF groups. Moreover, protein expression of COX2/b, LIF/b and p53/b increased following treatment with PRP in the RIF group with the endometrium thickness < 7mm. PRP enhances expression of LIF, COX2, p53, ERs and PRs in the RIF patients with thin endometrium which may improve endometrium receptivity.

Impact of the CPS-EG score as a new prognostic biomarker in triple-negative breast cancer patients who received neoadjuvant chemotherapy

BackgroundThis study aimed to establish risk groups on the basis of CPS-EG scores, independent of pCR status, in triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NACT) to identify the prognostic impact of the CPS-EG score.MethodsPatient characteristics included age, menopausal status, clinical stage, pathological stage, estrogen receptor (ER) expression, nuclear grade, Ki-67 proliferation index, residual cancer burden (RCB) score, HER2 status, and other tumor characteristics. The CPS-EG scoring system included clinical stage, pathological stage, ER status, and grade. Patients were divided into two groups on the basis of their CPS-EG scores ≤ 3 and > 3.ResultsA total of 148 patients who were diagnosed with TNBC and treated with NACT were included in the study. A total of 52.0% of the patients had a CPS-EG score of ≤ 3, whereas 48.0% had a score of > 3. The rate of patients who achieved pCR was 29.7% (n = 44). CPS-EG score (HR: 2.331; 95%CI; 1.179–4.608; p = 0.015), pCR (HR: 0.348; 95%CI; 0.144–0.844; p = 0.019), pre-treatment mKi-67 proliferation index (HR: 0.467; 95%CI; 0.251–0.871; p = 0.017), and RCB score (HR: 0.401; 95%CI; 0.174–0.923; p = 0.032) were identified as significant prognostic factors for 5-year DFS. For 5-year OS, significant prognostic factors were CPS-EG score (HR: 2.30; 95%CI; 1.036–4.799; p = 0.040) and pre-treatment mKi-67 proliferation index (HR: 0.484; 95%CI; 0.246–0.954; p = 0.036).ConclusionsThe CPS-EG score, pre-treatment mKi-67 level, and the pCR and RCB score were practical prognostic markers for long-term survival. Conversely, the prognostic significance of pCR status was diminished, particularly in predicting OS. These findings underscore the importance of not only post-treatment pathological staging but also the initial tumor stage and biological characteristics of the tumor in predicting ultimate survival outcomes following neoadjuvant chemotherapy in TNBC patients.

Protective Effects of 17-βE2 on the Primary Hepatocytes of Rainbow Trout (Oncorhynchus mykiss) Under Acute Heat Stress

The rainbow trout (Oncorhynchus mykiss) is a typical cold-water species. However, due to global warming, it has experienced prolonged high-temperature stress. Research indicates that thermotolerance in rainbow trout varies by sex at multiple physiological levels. Specifically, females exhibit higher thermotolerance, which may be attributed to estrogen-mediated signal transduction pathways. This study involved culturing primary hepatocytes from rainbow trout and exposing them to estradiol and estrogen receptor antagonists to assess estradiol’s protective effects. The analysis focused on expression of ER, HSPs genes, hepatocyte viability, and antioxidant indices. Four experimental groups were treated with 17-βE2 at concentrations of 0, 0.1, 1, and 10 μM/mL for durations of 4, 8, 12, 24, and 48 h at 18 °C. 17-βE2 treatment led to increased hepatocyte viability and enhanced SOD, GSH-Px, and CAT levels but decreased MDA levels. hsp70a, hsp90β, era1, and erβ1 levels were notably higher, with the optimal 17-βE2 concentration being 1.0 μM/mL. Following heat stress (24 °C), the addition of 1.0 μM/mL 17-βE2 improved hepatocyte viability and increased SOD, GSH-Px, and CAT levels, while MDA content initially decreased before rising. The gene expression of hsp70a, hsp90β, era1, and erβ1 was significantly elevated compared to controls. Flow cytometry analysis showed increased apoptosis after heat exposure; however, 17-βE2 treatment significantly reduced the heat stress-induced effects (p &lt; 0.05). In conclusion, 17-βE2 and mild heat stress collaboratively enhanced the expression of HSPs and estrogen receptors, thereby providing protection to hepatocytes from heat stress damage, indicating a beneficial protective role of estradiol in rainbow trout hepatocytes.

Effects of Lupeol on Estrogen and Androgen Receptor-Positive Breast and Prostate Cancer Cells

Background: Different reports have shown that prostate and breast cancers are the most common cancers worldwide. Lupeol, a dietary triterpene, provides various beneficial effects including anti-cancer properties. The current study aims to investigate the anti-proliferative and antioxidant effects of lupeol, in line with the effects of lupeol on the expression of estrogen and androgen receptors in breast (MCF-7) and prostate (LNCaP) cancer cell lines. Methods: MCF-7 and LNCaP cells were incubated with increasing concentrations of the lupeol (1, 10, and 100 µM) for 24h. The cytotoxicity of the lupeol was assessed by MTT and Neutral Red assays. Moreover, TAC (total antioxidant capacity), and gene expression of androgen and estrogen receptors were measured by spectrophotometric and qPCR methods, respectively. Overall, 17 beta-estradiol (E2) (9 nM) and dehydroepiandrosterone (DHEA) (5 µM) were selected as positive controls. Results: The highest concentration of the lupeol induced cytotoxic effects on MCF-7 and LNCaP cells. Various levels of lupeol at specified time intervals increased TAC levels in comparison with the control group. Moreover, the expression levels of estrogen receptors (α and β) and androgen receptors were negatively affected by lupeol. Conclusion: The findings of our study indicate that lupeol could serve as a promising, and accessible multi-functional anti-tumor agent against hormone-positive breast and prostate cancers.

Protein expression of estrogen, progesterone, and human epidermal growth factor receptors in young Iraqi women with breast cancer

Breast cancer is currently evaluated by the presence of hormonal receptors in the tumor tissue, which are among the most important prognostic and predictive markers used at present. The current study was conducted in Thi-Qar Governorate (Iraq) on women aged 20-40 years who have breast cancer (BC), highlighting­ the spread of this disease among young groups. The expression of estrogen (ER), progesterone (PR), and human epidermal growth factor (Her2/neu) receptors in breast tissues using immunohistochemical analysis was estimated. Breast tissue samples were collected from patients undergoing breast surgery and biopsy. Formalin-fixed paraffin-embedded samples were divided into BC (80), and control (20) groups. The study found that protein expression of both ER and PR was positive in 87.5% and negative in 12.5%, Her2/neu positive in 60% and negative in 40% of BC samples. The subtypes identified were luminal A (58.75%), luminal B (31.25%), HER2-positive (6.25%), and triple-negative (3.75%) BC. The high percentage of luminal A molecular subtype of BC is considered a good prognosis and treatable by anti-hormonal therapy. Keywords: breast cancer, estrogen, human epidermal growth factor, immunohistochemistry, progesterone, receptors

UL16‑binding protein 1 is a significant prognostic and diagnostic marker for breast cancer.

The aim of the present study was to investigate the association between UL16 binding protein 1 (ULBP1) and the prognosis of patients with and immune cell infiltration in breast cancer (BRCA). The mRNA data of BRCA and immune-related genes were extracted from The Cancer Genome Atlas and were analyzed using bioinformatics tools. Subsequently, the results obtained by bioinformatics were validated through the collection of clinical patient data at the Zibo Central hospital (Zibo, China). The difference in the expression of the ULBP1 gene between BRCA tissues and normal precancerous tissues was analyzed, followed by validation using immunohistochemistry. By combining clinical data from patients with BRCA, the prognostic and diagnostic significance of the ULBP1 gene in patients with BRCA was analyzed. Gene enrichment analysis was conducted to gain insight into the molecular mechanisms underlying the regulatory role of ULBP1 in BRCA by analyzing its related functions and signaling pathways. Furthermore, single sample gene set enrichment analysis (ssGSEA) and Spearman's correlation analysis were performed to explore the correlation between ULBP1 as a target gene related with tumor immune cell infiltration. The data revealed that ULBP1 is a target gene associated with immunity and the prognosis of patients with BRCA. Patients with BRCA with a high expression of ULBP1 had a poorer prognosis. ULBP1 expression correlated with progesterone receptor expression, estrogen receptor expression and histological type in patients with BRCA; thus, it may serve as an independent predictor for the overall survival rate of patients. Functional enrichment analysis revealed a significant co-expression between ULBP1 and ULBP2, ULBP3, retinoic acid early transcript 1K, as well as a significant enrichment of pathways associated with carcinogenesis and immune suppression. ssGSEA and Spearman's correlation analysis demonstrated significant correlations between ULBP1 expression and tumor immune cells, as well as immune checkpoints. Overall, the present study demonstrated that ULBP1 was associated with BRCA immunity and might serve as a prognostic and diagnostic biomarker for patients with BRCA. In addition, it might also be a potential target for the immunotherapy of BRCA.

Endometrial Dysbiosis: A Possible Association with Estrobolome Alteration

Background/Objectives: Microbiota modification at the endometrial level can favor gynecological diseases and impair women’s fertility. The overgrowth of pathogen microorganisms is related to the contemporary alteration of estrogen-metabolizing bacteria, including β-glucuronidase, thereby enhancing estrogen-related inflammatory states and decreasing anti-inflammatory cells. The possible connection between estrobolome impairment and gynecological diseases has been suggested in animal models. Nevertheless, in humans, coherent evidence on the estrobolome alteration and functionality of the female reproductive tract is still lacking. The objective of this study was to explore alterations in estrogen-related signaling and the putative link with endometrial dysbiosis. Methods: Women with infertility and repeated implantation failure (RIF, N = 40) were enrolled in order to explore the putative link between estrogen metabolism and endometrial dysbiosis. Endometrial biopsies were used to measure inflammatory and growth factor molecules. β-glucuronidase enzyme activity and estrogen receptor (ER) expression were also assessed. Results: Herein, increased levels of inflammatory molecules (i.e., IL-1β and HIF-1α) and decreased levels of the growth factor IGF-1 were found in the endometrial biopsies of patients presenting dysbiosis compared to eubiotic ones. β-glucuronidase activity and the expression of ERβ were significantly enhanced in patients in the dysbiosis group. Interestingly, Lactobacilli abundance was inversely related to β-glucuronidase activity and to ERβ expression, thus suggesting that an alteration of the estrogen-activating enzyme may affect the expression of ERs as well. Conclusions. Overall, these preliminary data suggested a link between endometrial dysbiosis and estrobolome impairment as possible synergistic contributing factors to women infertility and RIF.

DAB2IP Loss in Luminal A Breast Cancer Leads to NF-kB Associated Aggressive Oncogenic Phenotypes.

Despite proven therapy options for estrogen receptor (ER)-positive breast tumors, a substantial number of ER+ cancer patients exhibit relapse with associated metastasis. Loss of expression of RasGAPs leads to poor outcomes in several cancers, including breast cancer. Mining the TCGA breast cancer RNA-sequencing dataset revealed that low expression of the RasGAP DAB2IP was associated with a significant decrease in relapse-free survival in Luminal A breast cancer patients. Immunostaining demonstrated that DAB2IP loss occurred in grade 2 tumors and higher. Consistent with this, genes upregulated in DAB2IP-low Luminal A tumors were shared with more aggressive tumor subtypes and were associated with proliferation, metastasis, and altered ER signaling. Low DAB2IP expression in ER+ breast cancer cells was associated with increased proliferation, enhanced stemness phenotypes, and activation of IKK, the upstream regulator of the transcription factor NF-kB. Integrating cell-based ChIP-sequencing with motif analysis and TCGA RNA-seq data, we identified a set of candidate NF-kB target genes upregulated with loss of DAB2IP linked with several oncogenic phenotypes, including altered RNA processing. This study provides insight into mechanisms associated with aggressiveness and recurrence within a subset of the typically less aggressive Luminal A breast cancer intrinsic subtype.

The prognostic and immune significance of Rab11A in pan-cancer and its function and mechanism underlying estrogen receptor targeting in breast cancer.

Rab11A is an important molecule for recycling endosomes and is closely related to the proliferation, invasion, and metastasis of tumors. This study investigated the prognostic and immune significance of Rab11A and validated its potential function and mechanism in breast cancer (BRCA). RNA sequencing data for 33 tumors were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression databases. Correlation analysis was used to evaluate the relationship between Rab11A expression and immune characteristics. Potential pathways were identified using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis. Immunohistochemical analysis, colony formation assay, bromodeoxyuridine incorporation assay, immunofluorescence, and Western blot were used to explore potential function and mechanism. Analysis of the TCGA database showed significant upregulation of Rab11A expression in a variety of cancers. Rab11A was up-regulated in 82.4% of BRCA. High Rab11A expression is associated with poor survival in cancer patients and is a predictor of poor prognosis. CIBERSORT analysis showed that Rab11A was negatively associated with almost all immune cycle activity scores pan-cancer. The results of the TCGA-BRCA cohort were further confirmed by using pathological samples from clinical BRCA patients. The results showed that Rab11A expression was correlated with estrogen receptor (ER) and progesterone receptor expression in BRCA (p<0.05). Knockdown and overexpression of Rab11A affected the proliferation of BRCA cells. Further mechanistic studies revealed that down-regulation of ER alpha (ERα) and up-regulation of ER beta (ERβ) mediated Rab11A-induced inhibition of BRCA cell proliferation. Rab11A expression in pan-cancer is associated with poor prognosis and immune profile. In particular, in BRCA, Rab11A expression regulates cell proliferation by targeting ERα and ERβ. High Rab11A expression is tightly associated with immune characteristics, tumor microenvironment, and genetic mutations. These results provide a reference for exploring the role of Rab11A in pan-cancer and provide a new perspective for revealing potential therapeutic targets in BRCA.

Correlation analysis of Ki67 changes with survival outcomes in breast cancer before and after neoadjuvant therapy based on residual cancer Burden grade

PurposeThis study aims to investigate the change of Ki67 value pre- and post-neoadjuvant therapy (NAT) and evaluate its potential value in predicting survival outcomes in different molecular subtypes of breast cancer. MethodsA total of 257 breast cancer patients who underwent NAT at Renmin Hospital of Wuhan University from July 2019 to Sep 2023 were included in this study. The Ki67 index of the patients was re-interpreted by two attending physicians, and the changes of Ki67 value pre- and post-NAT were compared. Chi-square test (χ2) and logistic regression were conducted to examine the correlation between various characteristics and the efficacy of NAT. Disease-free survival (DFS) was calculated using the Kaplan-Meier curve and compared using the log-rank test. ResultsPatients with higher histological grade, negative expression of estrogen receptor (ER) or progesterone receptor (PR), positive expression of human epidermal growth receptor 2 (HER2), higher pretreatment Ki67 index, absence of lymph node metastasis, and those with HER2 positive and triple-negative breast cancer were associated with improved efficacy of NAT. Our study identified that the optimal cut-off value for the changes in Ki67 index pre- and post-NAT related to the effectiveness of NAT was “-88.19 %” in whole chort, which was related to the aforementioned clinical characteristics. Besides, the optimal cut-off values for the luminal, HER2-enriched and triple-negative subtypes were “-91.83 %”, “-46.12 %” and “-81.67 %”, respectively. Survival analysis demonstrated that the changes in Ki67 value were significantly associated with DFS in the HER2-enriched and triple-negative subtype, but not in the luminal subtype. ConclusionsPreoperative clinicopathological features and changes in Ki67 value pre-and post-NAT can contribute to providing patients with a more accurate prognosis.

Structural and functional features of the endometrium in chronic endometritis and implantation failure in IVF cycles

BACKGROUND: Implantation failure of the endometrium in women with chronic endometritis remains a subject of discussion, despite certain progress in the diagnosis and treatment of this pathology. It has been proven that chronic endometritis is a predictor of endometrial dysfunction, which contributes to the disruption of the morphogenesis of the endometrium necessary for its implantation capacity. Implantation disorders associated with chronic endometritis are related to pathology of the receptor profile and vascular bed, as well as dysregulation of proliferative and apoptotic mechanisms. AIM: The aim of this study was to evaluate the expression of estrogen and progesterone receptors, endothelial marker and apoptosis-inducing factor in the endometrium of patients with chronic endometritis and ineffective embryo transfer in IVF protocols. MATERIALS AND METHODS: This study enrolled 50 patients with ineffective embryo transfers in IVF protocols and 25 women in the control group with positive reproductive outcomes. All patients underwent a comprehensive morphological study of the endometrium including histological examination, immunohistochemical study with assessment of the receptor profile [estrogen (ERα) and progesterone (PR) receptor expression], chronic endometritis (CD8+, CD4+, CD20+, CD138+), apoptosis [antibodies to apoptosis-inducing factor (anti-AIF [E20])], and angiogenesis (CD34+), with microscopic, morphometric and statistical methods used as well. RESULTS: Endometrial implantation failure is associated with a history of urogenital infection, benign cervical diseases, high incidence of endometrial pathology and reproductive loss. It is characterized by the presence of follicle-like mononuclear infiltrates in the endometrium, fibroplastic changes in the stromal component, vascular sclerosis, abnormal increase in the pro-inflammatory cell count, multifocal decrease in estrogen (ERα) and progesterone (PR) receptor expression, as well as activation of pathological neoangiogenesis and apoptosis in the stroma. CONCLUSIONS: Chronic endometritis leads to disruption of the structural and functional characteristics of the endometrium, stimulates pathological neoangiogenesis and dysregulates proliferative and apoptotic mechanisms, which forms a vicious circle of endometrial implantation failure and inefficiency of embryo transfer in IVF protocols.

Monocyte subsets in breast cancer patients under treatment with aromatase inhibitor and mucin-1 cancer vaccine

BackgroundMonocytes comprise subsets of classical, intermediate and non-classical monocytes with distinct anti- or pro-tumor effects in breast cancer (BC). They are modulated by estrogen, and can contribute to BC control by endocrine therapy in preclinical models.MethodsTo elucidate whether changes in monocyte subsets are associated with treatment and response, we investigated peripheral blood samples of 73 postmenopausal women with estrogen receptor (ER) positive BC, who received aromatase inhibitor therapy with or without the mucin-1 vaccine tecemotide in the ABCSG34 trial. Blood was retrieved at baseline, midterm and end of therapy, and was analyzed for the distribution and ER expression of monocyte subsets by flow cytometry.ResultsWhen 40 healthy, age-matched women were compared with BC patients before treatment start, ER levels of monocytes did not differ, yet patients presented with a higher frequency of classical and fewer non-classical monocytes. Endocrine therapy triggered a significant increase in ER levels in all monocyte subsets, without affecting subset distribution. Vaccination had no overall impact on subset frequency and ER expression. Yet, a shift from intermediate to classical monocytes during therapy correlated with changes in plasma cytokines and chemokines and was significantly associated with low residual cancer burden in vaccinated patients. Without tecemotide, baseline ER levels in classical monocytes were significantly higher in women with good response to endocrine therapy.ConclusionsThis study identified classical monocytes to be associated with ER positive BC and with patient response to neoadjuvant endocrine treatment and cancer vaccination.

The Analysis Study of Cell Adhesion Molecules and Estrogen Receptor Expression In The Endometrium of Patients With Polycystic Ovary Syndrome: A Comprehensive Systematic Review

Introduction: Polycystic Ovary Syndrome (PCOS) is a multifaceted endocrine disorder affecting up to 7% of women in their reproductive years. Research on estrogen receptor expression and cell adhesion molecules in the endometrium is increasing, focusing on their roles in endometrial growth and embryo implantation. Despite insights, studies investigating these endometrial changes in PCOS are limited. Methods: This systematic review follows the PRISMA 2020 guidelines to analyze the relationship between cell adhesion molecules, estrogen receptor expression, and endometrial characteristics in patients with PCOS. Results: Eight relevant publications were identified after thorough screening from reputable sources. The included studies contribute to understanding the association between estrogen receptor gene variants and PCOS through various research approaches, highlighting significant findings related to estrogen receptor expression, cellular adhesion markers, and their implications on fertility. Conclusion: Variations in ESR1 and ESR2 gene SNPs are associated with altered protein structures that may contribute to PCOS pathogenesis. Genetic and molecular mechanisms identified in this review indicate how these variations can influence PCOS phenotypes and highlight the need for further research to develop targeted therapies.

7143 Near Term Cardiometabolic Outcomes in Transgender Boys and Men in the First Year of Gender-Affirming Testosterone Therapy

Abstract Disclosure: J. Dey: None. M. Widlansky: None. S. Cabrera: None. Background: Gender affirming testosterone (T) therapy is used to masculinize transgender adolescent men (TMs), resulting in elevated T and suppressed estradiol (E2). In cis-females, hypoestrogenism reduces vaso-protective E2-mediated estrogen receptor expression, decreasing nitric oxide vasodilation and increasing susceptibility to future vascular complications. Whether T promotes similar changes in TMs remains poorly understood. Methods: A longitudinal observational study is conducted in TMs aged 12-30yrs over the 1st yr of T, with visits at baseline (BL; pre-T), 6mo, and 1yr, compared to cis-males (CMs) with endogenous T. Primary outcome is change in brachial artery flow-mediated dilation (FMD%), an in vivo measure of vascular endothelial health, after 1yr of T. To detect a significant relative change in FMD%, 60 participants are needed (40 TMs, 20 CMs). Metabolic profile is assessed by fasting lipids, glucose, and insulin. Body composition is assessed by BMI and DEXA. Differences in mean values between and within a cohort were analyzed using the unpaired two-tailed T-test assuming unequal and equal variances, respectively. Results: To date, 51 participants are enrolled; the 21 participants who fully completed the study are included here (13 TMs, 8 CMs). At BL, TMs were post-menarchal with a mean age of 15.6yrs, ht 162.6cm, and BMI z-score 0.47. At BL, 46% were on progestin-only menstrual suppression. CMs had a mean age of 18.4yrs, ht 170.7cm, and BMI z-score 0.13. Cohorts were similar for age, height, and BMI.At BL, FMD% was higher in TMs than CMs (8.2 vs 4.6, p=0.01) but not at 1yr (6.9 vs 6.2, p=0.6). FMD% did not change in TMs receiving T over 1yr (8.2 vs 6.9, p=0.3). At BL, the brachial artery resting diameter (mm) was lower in TMs than CMs (2.6 vs 3.5, p&amp;lt;0.01) and remained such at 1-yr. Resting diameter increased in TMs over 1yr of T (2.6 vs 3.1, p&amp;lt;0.01) but not in CMs. There were no differences in resting or hyperemic flow velocity, or FMD (mm) between or within groups. At BL, % lean body mass (%LBM) was lower in TMs than CMs (60 vs 72, p&amp;lt;0.01) and estimated percent visceral adiposity tissue (%VAT) was higher (26 vs 14, p&amp;lt;0.01). In TMs, %LBM increased (60 vs 66, p &amp;lt;0.01) and %VAT decreased (26 vs 21, p&amp;lt;0.01) over 1yr of T, such that TMs and CMs were similar at 1yr. At BL, TMs had lower T but similar E2 (46 vs 27 pg/mL, p=0.2) to CMs. At 1-yr, TMs and CMs had similar T (556 vs 574 ng/dL, p=0.9) and E2 (52 vs 29, p=0.1). In TMs, T did not change E2. Lipid and glycemic indices did not change over 1yr in TMs. Conclusion: Initial analyses suggest that T does not affect FMD; however, FMD% interpretation is confounded by the small number of participants, progestins at BL in TMs, and the lower resting brachial artery diameter in TMs. The stable E2 in TMs on T may explain the stable FMD%. Overall, our findings suggest T results in relative stability of vascular and metabolic function and a beneficial shift in body composition in TMs. Presentation: 6/2/2024

Tibolone treatment after traumatic brain injury exerts a sex-specific and Y chromosome-dependent regulation of methylation and demethylation enzymes and estrogen receptors in the cerebral cortex

Tibolone, a synthetic steroid used for the treatment of climacteric symptoms, displays sex-specific protective actions in experimental models of brain diseases. Previous in vitro findings suggest that tibolone reduces oxidative stress and neuroinflammation through the regulation of DNA methylation and the activation of estrogen receptors (ERs) α and β. In this study, we assessed whether tibolone regulates the expression of genes coding for DNA methylation and demethylation enzymes and ERs in the injured cerebral cortex of animals suffering a traumatic brain injury. The four-core genotype mouse model was used to determine whether the effect of tibolone on gene regulation was influenced by gonads or by cell-autonomous actions of sex chromosomes. Tibolone treatment resulted in sex-specific modification in the expression of genes coding for DNA methyl transferases (Dnmt) 3a, and 3b, for growth arrest and DNA-damage-inducible proteins (Gadd) 45β and 45γ, and for ERα and ERβ. In contrast, tibolone did not affect the expression of genes coding for Dnmt1, Gadd45α, and ten-eleven translocation methylcytosine dioxygenases 1–3. The sex-specific effect of tibolone on Dnmt3a expression depended on gonadal sex. In contrast, the presence or absence of the Y chromosome determined the effect of tibolone on Dnmt3b, Gadd45β, Gadd45γ, ERα and ERβ expression. These findings suggest that tibolone exerts a sex-specific regulation of DNA methylation and ER expression in the injured cerebral cortex that is determined by a combination of gonadal effects and cell-autonomous actions of sex chromosome genes.

Correlation of Androgen Receptor Expression With Ki67 Proliferative Index and Other Clinicopathological Characteristics in Invasive Mammary Carcinomas.

Introduction The clinical importance of androgen receptor (AR) status in breast cancer is uncertain. The existing knowledge regarding the association of androgen receptor expression with clinicopathological factors of breast cancer is also limited. The main aim of this study is to evaluate the AR expression in breast cancer and to correlate it with the Ki67 proliferative index and other clinicopathological prognostic factors. Methods Theexpression of AR was evaluated in 192 invasive mammary carcinoma cases and the expression patterns were correlated with various clinicopathological prognostic factors such as age, tumor size, pathological primary tumor (pT) stage, nodal status,histological grade, estrogen receptor (ER) expression, progesterone receptor (PgR) expression, human epidermal growth factor receptor 2 (Her2) status, molecular subtype, and Ki67 labeling index. Immunohistochemistry was performed to assess AR, ER, PgR, Her2, and Ki67 expression. The clinicopathological data required for the analysis were obtained from the laboratory information system. Results Out of the 192 breast carcinoma cases, 139 (72.4%) showed AR-positive expression. The average age of the AR-positive cases was slightly higher than the AR-negative cases. AR-positive tumors tended to have a lower histological grade and positive ER and PgR expression. The expression of ARdid not correlate with tumor size, pT stage, nodal status, Her2 status, and Ki67 labeling index. Conclusion The expression of AR is noted in a significant proportion of breast carcinoma cases. AR expression may be related to good prognostic factors such as ER expression, PgR expression, and lower histologic grade. We also observed that AR expression did not have any association with the Ki67 proliferative index.

Estrogen receptors and vascular aging

After years of studying cardiovascular diseases (CVD) in men due to their higher incidence compared to women, attention is now being paid to female CVD and their pathophysiology. Even though premenopausal women have a lower incidence of CVD, this disparity progressively diminishes after menopause, highlighting the key role of sex hormones. Many preclinical and fundamental studies have demonstrated protective effects of estrogens on arterial endothelium, suggesting that hormone therapy could improve cardiovascular health in menopausal women. However, disappointing outcomes from a major clinical trial two decades ago questioned the cardiovascular protection by estrogens with age. In this review, we will summarize the main clinical and experimental studies reporting the effects of estrogens on CVD, with a focus on their impact on endothelial function. Then, we will present abnormalities in the expression and signaling of estrogen receptors (ERs) in the arteries, and the contribution of conventional estrogens to arterial protection during aging. Finally, we will examine how recent advances in the mechanisms of action of ERa could help to optimize hormone therapy for menopause.

Site-specific O-GlcNAcylation of progesterone receptor (PR) supports PR attenuation of interferon stimulated genes (ISGs) and tumor growth in breast cancer

Hormone receptor (HR) positive breast cancer, defined by expression of estrogen (ER) and/or progesterone (PR) receptor expression, is the most commonly diagnosed type of breast cancer. PR alters the transcriptional landscape to support tumor growth in concert with or independent of ER. Thus, understanding the mechanisms regulating PR function are critical to developing new strategies to treat HR+ breast cancer. O-GlcNAc is a post-translational modification responsible for nutrient sensing that modulates protein function. Although PR is heavily post-translationally modified, through phosphorylation and O-GlcNAcylation, specific sites of O-GlcNAcylation on PR and how they regulate PR action, have not been investigated. Using established PR-expressing breast cancer cell lines, we mapped several sites of O-GlcNAcylation on PR. RNA-sequencing after PR O-GlcNAc site mutagenesis revealed site-specific O-GlcNAcylation of PR is critical for ligand-independent suppression of interferon signaling, a regulatory function of PR in breast cancer. Furthermore, O-GlcNAcylation of PR enhances PR-driven tumor growth in vivo. We have delineated one contributing mechanism to PR function in breast cancer that impacts tumor growth, and provided additional insight into the mechanism through which PR attenuates interferon signaling.

Hypertension disrupts the vascular clock in both sexes.

Blood pressure (BP) displays a circadian rhythm and disruptions in this pattern elevate cardiovascular risk. Although both central and peripheral clock genes are implicated in these processes, the importance of vascular clock genes is not fully understood. BP, vascular reactivity, and the renin-angiotensin-aldosterone system display overt sex differences, but whether changes in circadian patterns underlie these differences is unknown. Therefore, we hypothesized that circadian rhythms and vascular clock genes would differ across sex and would be blunted by angiotensin II (ANG II)-induced hypertension. ANG II infusion elevated BP and disrupted circadian patterns similarly in both males and females. In females, an impact on heart rate (HR) and locomotor activity was revealed, whereas in males hypertension suppressed baroreflex sensitivity (BRS). A marked disruption in the vascular expression patterns of period circadian regulator 1 (Per1) and brain and muscle aryl hydrocarbon receptor nuclear translocator like protein 1 (Bmal1) was noted in both sexes. Vascular expression of the G protein-coupled estrogen receptor (Gper1) also showed diurnal synchronization in both sexes that was similar to that of Per1 and Per2 and disrupted by hypertension. In contrast, vascular expression of estrogen receptor 1 (Esr1) showed a diurnal rhythm and hypertension-induced disruption only in females. This study shows a strikingly similar impact of hypertension on BP rhythmicity, vascular clock genes, and vascular estrogen receptor expression in both sexes. We identified a greater impact of hypertension on locomotor activity and heart rate in females and on baroreflex sensitivity in males and also revealed a diurnal regulation of vascular estrogen receptors. These insights highlight the intricate ties between circadian biology, sex differences, and cardiovascular regulation.NEW & NOTEWORTHY This study reveals that ANG II-induced hypertension disrupts the circadian rhythm of blood pressure in both male and female mice, with parallel effects on vascular clock gene and estrogen receptor diurnal patterns. Notably, sex-specific responses to hypertension in terms of locomotor activity, heart rate, and baroreflex sensitivity are revealed. These findings pave the way for chronotherapeutic strategies tailored to mitigate cardiovascular risks associated with disrupted circadian rhythms in hypertension.

Developing & Validating a Clinical Decision Support Tool for ER-targeted PET Imaging with 16α-18F-Fluoro-17β-Fluoroestradiol

BackgroundEstrogen receptor (ER) status in breast cancer (BC) is routinely determined by immunohistochemistry (IHC); however, this technique is not without limitations, including false results. Imaging of CeriannaTM (fluoroestradiol F18) injection provides high diagnostic accuracy of ER expression, supplementing information from biopsy. A Clinical Decision Support (CDS) tool was developed to better assess its clinical usefulness in metastatic and recurrent breast cancer management. This study evaluated a conceptual tool that reflects clinical practice variables. MethodsIndividual patient characteristics - candidacy for therapeutic treatment and rate of recurrence - determined initial eligibility. The CDS tool uses rules (IF-THEN statements) to produce an output on the diagnostic accuracy of ER status based on tumor burden, anatomical location(s) of metastasis, heterogeneity, and confidence in sample collection & pathology accuracy (CSC & PA). An Excel-based probability decision tree calculates the accuracy of ER expression. Results360 oncologists in the United States participated in the survey study. 223 respondents identified as medical oncologists (62%), 77 as clinical oncologists (21%), and 60 as hematologic oncologists (17%). 93% of respondents found the CDS tool intuitive and easy to follow with medical and clinical oncologists favoring the tool more than hematologic oncologists. Individual CDS attributes - clinical criteria, diagnostic comparator, true positive and true negative, patient inclusion and exclusion, and clinical patient level inputs - were tested with overall positive feedback. ConclusionsBased on respondent feedback, further development of CDS tools are warranted for potential use in patients’ diagnostic workup. Micro abstractCorrect identification of estrogen receptor (ER) status in breast cancer is critical to optimal treatment decisions. While ER status is routinely determined by biopsy and immunohistochemistry (IHC), this technique may yield false positive or negative results. Cerianna (fluoroestradiol F18) injection provides high diagnostic accuracy of ER expression, supplementing the information obtained by IHC. A Clinical Decision Support tool was developed to help identify the contribution that Cerianna may contribute to the management of metastatic and recurrent breast cancer. This study incorporated the feedback of 360 Oncologists representing several sub-specialties, settings of care, and other variables. The results confirmed the validity of the CDS tool concluding that it resonates with clinical practice today, is complete and would be used in clinical practice.