Estrogen Receptor Levels Research Articles

Evaluation of polygenic risk scores for hormones and receptors levels in patients with vestibulodynia: a case-control study.

Vulvodynia is a multifactorial disease affecting 7%-16% of reproductive-aged women in general population; however, little is still known about the genetics underlying this complex disease. To compare polygenic risk scores for hormones and receptors levels in a case-control study to investigate their role in vulvodynia and their correlation with clinical phenotypes. Our case-control study included patients with vestibulodynia (VBD) and healthy women. All participants underwent a vestibular cotton swab test and the assessment of their: pelvic floor, vestibular trophism, ultrasound vestibular mucosa thickness, and current perception threshold levels (Neurometer CPT device). Shallow whole genome sequencing and polygenic risk score calculations were performed. Linear regression models were applied to predict whether genomic predisposition varied significantly between cases and controls, and to investigate the relationship of polygenic risk scores with clinical endophenotypes. The genomic predisposition to hormones and receptors levels, together with clinical endophenotypes, can support VBD diagnosis and personalized treatment of related pain condition. Thirty women with VBD and 30 controls were recruited. Significant differences between cases and controls were observed for body mass index, vestibular mucosa thickness, vestibular trophic health, pelvic floor hypertone and pain sensitivity (P < .05). Cases showed a genomic predisposition to higher levels of membrane-associated progesterone receptor component 1 compared to controls (P < .05). When considering the clinical endophenotypes, cases showed significant correlations between their polygenic risk scores with several clinical measures: predicted genomic levels of testosterone and estrogen receptor and the vestibular mucosa thickness values (estimates: 9.74E-09 and 9.16E-08, respectively; P < .05); predicted genomic levels of prolactin and Neurometer data at 250Hz (-2.15E-07; P < .05); predicted genomic levels of prolactin, membrane-associated progesterone receptor component 2 and mineralocorticoid receptor and Neurometer data at 5Hz (-3.75E-07, -3.43E-07 and -3.06E-07, respectively; P < .05). Introduction of polygenic risk scores evaluation in clinical practice can assist early diagnosis and personalized therapeutic treatment of VBD. Polygenic risk scores and clinical data allowed the identification of disease endophenotypes and highlighted the possibility of a personalized therapeutic approach. As limitations, these data should be confirmed on a larger cohort and polygenic risk score calculation should be adapted to ancestries other than European. Cases showed significant differences compared to controls on both clinical and genetic data and specific endophenotypes necessary to classify disease development and treatment were identified.

Association of Proteasome Activity and Pool Heterogeneity with Markers Determining the Molecular Subtypes of Breast Cancer.

Proteasomes degrade intracellular proteins. Different proteasome forms were identified. Proteasome inhibitors are used in cancer therapy, and novel drugs directed to specific proteasome forms are developed. Breast cancer (BC) therapy depends on the subtype of the tumor, determined by the expression level of Ki67, HER-2, estrogen and progesterone receptors. Relationships between the presence of specific proteasome forms and proteins that determine the BC subtype remain unclear. Here, using gene expression data in 19,145 tumor samples from 144 datasets and tissues from 159 patients with different subtypes of BC, we investigated the association between the activity and expression of proteasomes and levels of BC subtype markers. Bioinformatic analysis of proteasome subunit (PSMB1-10) gene expression in BC was performed. Proteasome heterogeneity in BC cell lines was investigated by qPCR. By Western blotting, proteasome composition was assessed in cells and patient tissue lysates. Proteasome activities were studied using fluorogenic substrates. BC molecular subtypes were determined by immunohistochemistry. BC subtypes demonstrate differing proteasome subunit expression pattern and strong PSMB8-10 co-correlation in tumors. A significant increase in chymotrypsin- and caspase-like proteasome activities in BC compared to adjacent tissues was revealed. The subunit composition of proteasomes in tumor tissues of BC subtypes varied. Regression analysis demonstrated a positive correlation between proteasome activities and the expression of Ki67, estrogen receptors and progesterone receptors. BC subtypes demonstrate differences within the proteasome pool. Correlations between the proteasome activity, hormone receptors and Ki67 indicate possible mutual influence. Obtained results facilitate development of novel drug combinations for BC therapy.

Gelatin/polycaprolactone membranes promote endometrial regeneration and restore fertility

Objective To investigate the effectiveness of gelatin/polycaprolactone (GT/PCL) membranes for restoring endometrial structure and function and fertility in a rat model of endometrial injury. Methods We randomized 125 female Sprague-Dawley (SD) rats to the sham, natural repair (NR), estrogen (E), GT/PCL, and E-GT/PCL groups. Except for the sham group, all rats underwent uterine curettage. After 1, 2, 3, and 4 weeks, 12 rats from each group were sacrificed; their uterine tissue was collected for histological, immunohistochemical, and reverse transcription quantitative-polymerase chain reaction analyses. Eight rats from each group underwent radiography of the uterine cavity. The remaining 25 females were mated with males to assess fertility 60 d postoperatively. Results The GT/PCL and E-GT/PCL groups had higher endometrial thickness, collagen degradation, cytokeratin 19, vimentin (VIM) expression, and microvessel densities and had higher levels of estrogen receptors (ERα) but lower levels of tumor necrosis factor (TNF) than the NR and E groups. They also showed better hysterographic patency, with the shape of the uterine cavity similar to that of the sham group, and higher embryo implantation rates than the NR and E groups. Conclusions GT/PCL membranes promote endometrial regeneration and improve fertility in rats. They may help prevent intrauterine adhesions (IUAs) postoperatively and warrant further investigation.

Acephate Exposure Induces Transgenerational Ovarian Developmental Toxicity by Altering the Expression of Follicular Growth Markers in Female Rats.

Acephate is an organophosphate foliar and soil insecticide that is used worldwide. In this study, the transgenerational ovarian developmental toxicity caused by acephate, along with its in utero reprogramming mechanisms, were explored. Thirty female virgin Wistar albino rats were randomly assigned to three groups: one control group and two acephate treatment groups. The treatment groups received daily low or high doses of acephate (34.2 mg/kg or 68.5 mg/kg body weight, respectively) from gestational day 6 until spontaneous labor, resulting in F1 offspring. At 28 days, a subgroup of F1 females were euthanized. The ovaries were extracted, thoroughly cleaned, and weighed before being fixed for further analysis. The remaining F1 females were mated with normal males to produce the F2 generation. The F1 female offspring presented reduced fertility and body weight, whereas the ovarian weight index and sex ratio increased in a dose-dependent manner. Structural analysis revealed altered follicular abnormalities with ovarian cells displaying pyknotic nuclei. Additionally, the gene and protein expression of Cyp19 decreased, whereas that of Gdf-9 increased in the high-dose treatment group (68.5 mg/kg). We also observed significantly increased expression levels of ovarian estrogen receptor 1 (Esr1) and insulin-like growth factor 1 (Igf1), whereas Insl3 expression was significantly decreased. The F2 female offspring presented reproductive phenotype alterations similar to those of F1 females including decreased fertility, reduced Cyp19 gene and protein expression, and structural ovarian abnormalities similar to those of polycystic ovary syndrome (PCOS). In conclusion, acephate induced ovarian developmental toxicity across two generations of rats, which may be linked to changes in the ovarian Cyp19, Gdf9, Insl3, and Igf1 levels.

Detection of Circulating Tumor Cells in the Prognostic Significance of Patients With Breast Cancer: A Retrospective Study.

Breast cancer (BC) is an aggressive tumor. Circulating tumor cells (CTCs) are a potential biomarker for the prognosis of cancer patients. This study aimed to explore the prognostic significance of CTCs in patients with BC. Retrospectively, 108 BC patients were collected between January 2011 and December 2019, while 10 patients with benign nodules were included as controls. CTCs with different phenotypes of patients were isolated using CanPatrol and tricolor RNA insitu hybridization (RNA-ISH) methods. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2) levels were measured by immunohistochemistry (IHC). The progression-free survival (PFS) was calculated using the Kaplan-Meier method. Independent risk factors for BC recurrence were determined by Cox proportional risk regression analysis. The higher the cancer stage (p = 0.00), the higher the ki-67 expression level (p < 0.01), and the lower the histologic grade (p < 0.01), the higher the number of CTCs. The PFS of patients with high CTCs was shorter than that of patients with low CTCs (p < 0.05). Total CTCs (≥ 6) and positive mesenchymal CTCs (MCTCs) were also associated with recurrence and metastasis. Total CTCs in BC patients have an independent influence on PFS reduction. Higher total CTCs and MCTCs in peripheral blood are biomarkers for predicting the prognosis of BC patients. HER-2 high expression is also associated with the prognosis of the disease.

Investigating the role of oviductal mucosa-endometrial co-culture in modulating factors relevant to embryo implantation.

Intrauterine adhesions (IUAs) are a significant clinical challenge, affecting reproductive health and leading to infertility or recurrent pregnancy loss. Understanding the molecular mechanisms underlying IUA prevention is crucial for developing effective treatment strategies. To investigate the interaction between oviductal mucosal cells and endometrial cells and their effects on the expression of key molecules involved in embryo implantation, specifically leukemia inhibitory factor (LIF), avβ3, estrogen receptor (ER), and progesterone receptor (PR). Tubal mucosa and endometrium specimens were collected from 22 patients undergoing surgical interventions. Cells were cultured alone and co-cultured at ratios of 1:1, 1:0.5, and 1:0.1. LIF, avβ3, ER, and PR expression levels were measured using real-time fluorescence quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Our results demonstrated that LIF expression was significantly augmented in co-culture conditions, particularly in the 1:1 ratio, compared to oviductal mucosa monoculture (P < 0.05). Although LIF expression was also elevated in 1:0.5 and 1:0.1 co-culture ratios, these increases were not statistically significant (P > 0.05). For avβ3, increased expression was observed in the 1:1 co-culture group (P < 0.05), but no significant differences were detected in 1:0.5 and 1:0.1 co-culture groups. ER expression showed a downward trend in co-culture, but without statistical significance (P > 0.05), and PR expression remained stable across all groups. Co-culture modulates key molecules involved in embryo implantation, particularly LIF and avβ3. These findings highlight the potential roles of LIF and avβ3 in IUA prevention strategies and provide important insights for future clinical interventions. Tubal mucosal cells can not only grow in the endometrial cell microenvironment, but also the tolerance of tubal mucosal cells can be improved when they are co-cultured.

Loss of ERα involved-HER2 induction mediated by the FOXO3a signaling pathway in fulvestrant-resistant breast cancer

Patients with estrogen receptor alpha (ERα)-positive breast cancer are commonly treated with anti-estrogen drugs as an initial treatment strategy. Fulvestrant, an estrogen receptor antagonist, effectively blocks ERα signaling; however, long-term fulvestrant treatment induces drug resistance in the absence of ERα. In this study, we investigated the molecular mechanism underlying the loss of ERα, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ERα proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R. FOXO3a, a transcriptional regulator of ERα was decreased in Ful-R, and a ubiquitin-proteasome inhibitor restored the expression of FOXO3a. These results suggest that the suppression of FOXO3a and ERα led to the increased expression of TGF-α, EGFR, and HER2 and subsequent cell proliferation in Ful-R. This study highlights the potential development of therapeutic drugs targeting FOXO3a for the treatment of HER2-positive, estrogen, and progesterone receptor-negative her2-type proliferative breast cancers.

Enhanced physicochemical properties of isoflavone derivatives through enzymatic encapsulation using cyclodextrin glucanotransferase

To establish the encapsulation parameters applicable to isoflavones, inclusion complexes (cycloamylose-genistein (CA-GNT), CA-daidzein (CA-DDZ), CA-equol (CA-EQ)) were synthesized for three varieties of plant-derived isoflavones via the cyclization catalysis of cyclodextrin glucanotransferase (CGTase; EC 2.4.1.19). Subsequently, an analysis of their physicochemical properties and functional characteristics was performed to ascertain their retained intrinsic activity within the encapsulated milieu. These encapsulation complexes were purified via preparative high-performance liquid chromatography and confirmed through MALDI TOF mass spectrometry for molecular weight analysis. The water solubility of CA-GNT, CA-DDZ, and CA-EQ increased approximately 15,000, 89,000, and 90 times, respectively, compared to the original compounds. Furthermore, in a 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical scavenging activity assay, the CA-GNT, CA-DDZ, CA-EQ encapsulated complexes exhibited 6.4-, 6.9-, and 4.2-fold higher levels of scavenging activity compared to the original material in aqueous solution, respectively. The mRNA level of estrogen receptor α increased with increasing treatment concentration of the encapsulated complexes in MC3T3 cells, which was similar to the effect of the original compounds. CA-EQ remained stable under external conditions of varying pH and high temperature, and a decrease in nitric oxide (NO) production was observed as the treatment concentration increased in RAW 264.7 cells.

Tumor and peritumoral tissue hormonal background features in patients with rare types of endometrial cancer

Serous endometrial intraepithelial carcinoma (SEIC) and clear cell carcinoma of the endometrium (CCEC) belong to pathogenetic type II without evidence of hyperestrogenism, are often detected late in the course of the disease, and are characterized by an aggressive course. Currently, there is increasing interest in the role of local content and metabolism of steroid hormones in organs and tissues in various pathologies, including the development of malignant tumors. Purpose of the study. To determine the local level of sex hormones in patients with SEIC and CCEC. Patients and methods. The study included 21 patients with SEIC and 20 patients with CCEC. The control group consisted of 20 patients who had undergone surgical treatment for uterine myoma. All patients were treated at the National Medical Research Center for Oncology, Rostov‑on‑ Don, the Russian Federation Ministry of Health. The local levels of estrogens and androgens were determined in the tumor tissue, the perifocal zone, endometrial tissue unaffected by the tumor process, and the fallopian tube tissue in patients with SEIC and CCEC. In the control group, the local level of sex hormones was determined in intact 10 % homogenic endometrial tissue. Results. The data were analyzed, and the results demonstrated that the tumors and peritumoral tissues exhibited a depletion of estradiol (E2), a saturation of testosterone, and an extreme saturation of estriol (E3). The consequence of this imbalance was the predominance of fetal placental estrogen (E3), which was detected not only in the tumor tissue but also in distant parts of the endometrium and uterine tubes. In these regions, the concentration of E3 exceeded that of intact endometrium by a factor of more than five. A comparison of estrogen receptor (ER) levels revealed elevated levels in samples of the tumor, its perifocal zone, distant endometrium, and fallopian tubes. This finding indicated a predominance of ERα over ERβ. Conclusion. The local hormonal background of rare forms of non‑endometrioid endometrial carcinomas exhibits distinctive characteristics, including the replacement of the influence of classical estrogen (E2) by fetal, placental E3. Additionally, there is a notable prevalence of the REα type over REβ, along with hyperandrogenization of tissues, which culminates in the formation of a unique low‑differentiated tumor with pronounced biological aggressiveness.

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.

Dan’e fukang decoction reduces hemorrhage in a rat model of mifepristone induced incomplete abortion and may correlate with cell adhesion molecule signaling interference

Ethnopharmacological relevanceDan’e fukang decoction (DFD) is a traditional Chinese medicine formula. DFD obtains 10 herbs, including Salvia yunnanensis C.H.Wright (Zidanshen), Curcuma zedoaria (Christm.) Roscoe (Ezhu), Angelica sinensis (Oliv.) Diels (Danggui), Cyperus rotundus L. (Xiangfuzi), Corydalis yanhusuo (Y.H.Chou & Chun C. Hsu) W.T.Wang ex Z.Y.Su & C.Y.Wu, Bupleurum marginatum Wall. ex DC. (Yanhusuo), Sparganium stoloniferum (Buch.-Ham. ex Graebn.) Buch.-Ham. ex Juz. (Sanleng), Panax notoginseng (Burkill) F.H.Chen (Sanqi), Paeonia lactiflora Pall. (Shaoyao) and Glycyrrhiza uralensis Fisch. (Gancao). DFD is now clinically used for the treatment of menstrual irregularities, dysmenorrhea and menstrual discomfort caused by blood stasis and easing of endometriosis. Based on this, it is reasonable to presume that DFD may be effective in treating incomplete abortion and reducing postpartum bleeding, but no specific studies have been reported so far. Aim of the studyTo investigate the efficacy of Dan’e fukang decoction (DFD) in reducing prolonged vaginal bleeding followed by mifepristone induced incomplete abortion and explore the mechanisms of action of DFD in treating incomplete abortion. MethodsAn incomplete abortion model of rat was established by single intragastrically administered 8.5 mg/kg mifepristone on the 7th day of pregnancy. From the 8th day of pregnancy, the abortive rats were administered solvent, a positive control drug, or different doses of DFD, respectively for seven consecutive days. The efficacy of DFD was assessed by measuring the vaginal bleeding volume of the rats. Four coagulation parameters and platelet counts were measured. Hematoxylin and eosin (HE) staining was performed to evaluate pathological changes in the uterine embryos. Serum levels of progesterone and estrogen were measured using ELISA. Network pharmacology and transcriptomics were used to predict potential targets and pathways for DFD to reduce hemorrhage. The levels of mRNA related to cell adhesion molecules (CAMs) were detected by RT-qPCR. The levels of progesterone and estrogen receptors and the proteins associated with CAMs pathway in uterine tissues were detected by Western Blot. ResultsDFD significantly reduced the volume of vaginal bleeding of the abortive rats and significantly downgraded the pathological scores of uterine embryos. DFD significantly increased serum levels of E2, and had no impact on serum levels of P4 and the protein expression of ER and PR in the uteri of the abortive rats. Pathways in cancer, lipid, focal adhesion and immune-related signaling were predicted to be influenced by DFD via the analysis of network pharmacology. The CAMs signaling was found the most critical pathway regulated by both mifepristone and DFD via RNA-seq assay, followed by axon guidance, basal cell carcinoma, hippo signaling pathway and neuroactive ligand-receptor interaction. Combining the two analytical methods, ICAM-1 was predicted likely the key targeted gene by DFD. Finally, DFD was validated to decrease the protein expression of ICAM-1, ITGB2, ITGB7 and RASSF5 in the uterine tissues, which correlated to suppress the CAMs signaling pathway. ConclusionDFD significantly reduced hemorrhage. DFD significantly increased the serum levels of E2 and inhibited CAMs signaling pathway, which was likely to be involved in the mechanism of action of DFD facilitating residual uterine embryo expulsion in the rat model of incomplete abortion.

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 estrogen response in fibroblasts promotes ovarian metastases of gastric cancer

Younger premenopausal women are more prone to developing ovarian metastases (OM) of gastric cancer (GC) than metastases of other organs; however, the molecular mechanisms remain unclear. Here we perform single-cell RNA sequencing on 45 tumor samples from 18 GC patients with OM. Interestingly, fibroblasts in OM of GC express high levels of estrogen receptor (ER) and midkine (MDK), interacting with tumor cells through activating ER-MDK-LRP1 (low-density lipoprotein receptor-related protein 1) signaling axis. Functional experiments demonstrate that estrogen stimulation induces MDK secretion by ovarian fibroblasts, and binding of MDK to LRP1 increases GC cell migration and invasion. Furthermore, in vivo, estrogen stimulation remarkably augments ovarian engraftment and metastasis of LRP1+ GC cells. Collectively, our findings reveal that ER+ ovarian fibroblasts secrete MDK under estrogen influence, driving OM of GC via the MDK-LRP1 axis. Our study holds the potential to catalyze innovative therapeutic strategies aimed at intercepting and managing OM in GC.

Restorative effects of melatonin on bisphenol a-induced interference of gene expression in hypothalamic pituitary axis following early exposure

Bisphenol-A is a standard monomer used in manufacturing plastics and epoxy resins, and it is widely used in food preservation and packaging. It is an endocrine-disrupting chemical miming the endogenous estradiol hormone. Melatonin regulates sleep-wake cycles and plays essential physiological roles in the body through its antioxidative properties. This research aims to ascertain the impact of Bisphenol A on the hypothalamic-pituitary-ovarian axis and determine melatonin's function on possible BPA-induced effects. Six adult male Wistar rats and 12 adult female Wistar rats of proven fertility were bred and organized into groups. These animals were subjected to subcutaneous injections of high and low doses of bisphenol A from postnatal days 0-3, then oral melatonin. The rats were allowed to mature into full-grown adults and euthanized at 120 ±4 days. The serum and hypothalamic-pituitary-ovarian tissues were collected for various assays. Compared to the control groups, groups administered varying doses of bisphenol A showed significant overexpression of estrogen and androgen receptors. Administration of Melatonin showed some reversal and reparative effects on damage of the hypothalamic pituitary ovarian axis. Elevated estrogen receptor levels induced by Bisphenol A altered receptor function. Melatonin showed some promising reparative effects.

Pre-clinical Evaluation of Karanjin Against DMBA-Induced Breast Cancer in Female Sprague-Dawley Rats Through Modulation of SMAR1 and CDP/CUx genes.

To investigate the chemoprotective potential of karanjin against 7,12-dimethylbenz(α)anthracene (DMBA)-induced breast cancer. Thirty-six female rats were utilized for the study. Breast cancer was induced through a subcutaneous injection of 35mg/kg DMBA. The animals were allocated to six groups. Three groups were allocated for karanjin (50mg/kg, 100mg/kg, and 200mg/kg), and received daily treatment for 20weeks (including 2weeks as pre-treatment). Doxorubicin (4mg/kg) was administered to the standard control group twice a week for 20weeks. The disease control (DC) and normal control (NC) groups received daily treatment with saline. After the treatment, oxidative stress parameters, biochemical parameters, and inflammatory parameters were estimated. CCAAT-displacement protein/cut homeobox (CUP/Cux) and scaffold/matrix attachment region binding protein 1 (SMAR1) expression levels were measured through gene expression analysis. Immunohistochemical (IHC) analysis was performed to estimate the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Tumor growth reduced significantly (P-value < 0.01) in karanjin-treated animals compared to the DC group. Karanjin significantly (P-value < 0.01) regulated the levels of oxidative stress parameters, biochemical parameters, and inflammatory parameters compared to the DC group. Karanjin treatment significantly (P-value < 0.001) regulated the expression levels of SMAR1 and CDP/Cux. A notable reduction in the IHC scores was observed for ER, PR, and HER2 expression in karanjin groups. Karanjin demonstrated chemoprotective activity against DMBA-induced breast cancer in animals potentially through modulation of SMAR1 and CDP/Cux gene expression and reduction of ER, PR and HER2 expression levels.

Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.

ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS (P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS (P = .001) in models with ER. Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.

Estrogen and progesterone receptor expression: Impacts on platinum sensitivity and survival outcomes in high‐grade serous ovarian cancer

AbstractBackgroundThis study aimed to explore the impact of patient‐specific factors on the effectiveness of platinum‐based chemotherapy in ovarian cancer patients. Specifically, we investigated the relationship between estrogen receptor (ER) and progesterone receptor (PR) expression levels and platinum sensitivity, and how this influenced treatment outcomes and prognosis. We conducted a survival analysis on patients who underwent surgical treatment for serous ovarian cancer and received platinum‐based adjuvant therapies.MethodsThis study was a retrospective observational analysis of 171 patients with high‐grade serous ovarian cancer. We extracted and analyzed the patients' clinical data, focusing on platinum sensitivity concerning hormone receptor expression. We also assessed survival outcomes based on receptor expression and platinum resistance.ResultsOur findings revealed that 78.4% (n = 134) of the patients were platinum‐sensitive, while 21.6% (n = 37) were platinum‐resistant. The expression of hormone receptors showed significant associations with platinum sensitivity, particularly among ER‐positive patients (p &lt; 0.05). Age, disease stage, preoperative carbohydrate antigen 125 (CA125) levels, and residual tumor size were identified as notable factors influencing both progression‐free survival (PFS) and overall survival (OS). In terms of PFS, 88.5% of patients remained free from disease progression after one year, but this percentage dropped to 21% after five years. The average duration of PFS was 35.3 months. As for OS, 93.5% of patients were still alive after one year, but this percentage decreased to 50.5% after five years. The average survival duration was 64 months. Furthermore, platinum resistance was found to be a significant risk factor for disease progression, with a more than fivefold increase in risk (p &lt; 0.001).ConclusionOur study identified disease stage progression, ER negativity, and platinum resistance as the primary factors influencing OS. We also found that ER and PR expression played a crucial role in determining the sensitivity to platinum‐based chemotherapy in patients with serous ovarian cancer.

Predicting efficacy of neoadjuvant chemotherapy in breast cancer patients with synthetic magnetic resonance imaging method MAGiC: An observational cohort study

ObjectiveMAGnetic resonance Imaging Compilation (MAGiC) is typical method of synthetic magnetic resonance imaging (MRI). The present aimed to investigate the role of MAGiC parameters of relaxation time (T1), transverse relaxation time (T2) and proton density (PD) to predict the treatment efficacy of breast cancer patients after neoadjuvant chemotherapy (NAC). MethodsThe present prospective cohort study enrolled 120 breast cancer patients who received NAC during 2021–2023. Demographic data and clinical characteristics including tumor node metastasis (TNM) stage, pathological type, molecular classification and lymph node metastasis were collected. The levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) were measured. Patients were divided by treatment efficacy using the Miller-Payne grading as partial pathological response (pPR) group and pathological complete response (pCR). The values of MAGiC parameters of longitudinal T1, T2, and PD values were recorded. ResultsIn all 120 patients, 73 (60.83%) cases were with pPR and 47 (39.17%) cases were with pCR after treatment. T2 values were markedly lower in pPR patients compared with pCR patients. However, no significant difference was found for T1 and PD values. No significant correlation was observed between any of MAGiC parameters and HER-2, ER or PR. ROC curve showed T2 could be used for prediction of pPR with AUC 0.780. Lymph node metastasis and low levels of T2 were found as independent risk factors for pPR after treatment. ConclusionThe T2 value parameter from MAGiC is an independent risk factor for pPR following NAC in breast cancer patients, suggesting its potential as a biomarker for predicting treatment efficacy.

Effects of metal oxide inhalation on the transcription of some hormone receptors in the brain, examined in an in vivo mouse model

Respirable metal oxide nanoparticles in welding fumes pose significant health risks upon inhalation, potentially leading to neurodegenerative diseases. While the exact mechanisms remain unclear, it is evident that metal oxide nanoparticles can disrupt cellular functions, including metabolism and inflammatory responses after crossing the blood–brain barrier (BBB). Our study investigates the impact of manual metal arc welding fumes on hormone receptor transcription in an in vivo mouse model. After collecting samples from six different brain regions at 24 and 96 h upon exposure, we focused on expression levels of estrogen receptors (ERs), thyroid hormone receptors (TRs), and peroxisome proliferator-activated receptors (PPARs) due to their roles in modulating neuroprotective responses and neuroinflammatory processes. Analysis revealed differential susceptibility of brain regions to hormonal disruption induced by welding fumes, with the hypothalamus (HT) and olfactory bulb (OB) showing prominent changes in receptor expression. Considering ERs, 24 h sampling showed an elevation in OB, with later increases in both ERα and ERβ. HT showed significant ERβ change only by 96 h. TRs mirrored ER patterns, with notable changes in OB and less in HT. PPARγ followed TR trends, with early upregulation in HT and downregulation elsewhere. These findings suggest a compensatory response within the CNS aimed at mitigating neuroinflammatory effects, as evidenced by the upregulation of ERβ, TRα, and PPARγ. The coordinated increase in ERs, TRs, and PPARs in the hypothalamus and olfactory bulb also highlights their potential neuroprotective roles in response to welding fume exposure. Our results also support the theory of metal oxide penetration to the CNS via the lungs-blood-BBB pathway, making HT and OB more vulnerable to welding fume exposure.

CYB5R3 overexpression exhibits sexual dimorphism: Mitochondrial and metabolic adaptations in transgenic female mice during calorie restriction

There is a pressing need to develop new strategies for enhancing health in the elderly and preventing the rise in age-related diseases. Calorie restriction without malnutrition (CR) stands among the different antiaging interventions. Lifelong CR leads to increased expression and activity of plasma membrane CYB5R3, and male mice overexpressing CYB5R3 exhibit some beneficial adaptations that are also seen with CR. However, the mechanisms involved in both interventions could be independent since key aspects of energy metabolism and tissue lipid profile do not coincide, and many of the changes induced by CR in mitochondrial abundance and dynamics in the liver and skeletal muscle could be counteracted by CYB5R3 overexpression. In this study, we sought to elucidate the impact of CR on key markers of metabolic status, mitochondrial function, and pro-oxidant/antioxidant balance in transgenic (TG) female mice overexpressing CYB5R3 compared to their WT littermates. In females fed ad libitum, CYB5R3 overexpression decreased fat mass, led to a preferred utilization of fatty acids as an energy source, upregulated key antioxidant enzymes, and boosted respiration both in skeletal muscle and liver mitochondria, supporting that CYB5R3 overexpression is phenotypic closer to CR in females than in males. Whereas some markers of mitochondrial biogenesis and dynamics were found decreased in TG females on CR, as also found for the levels of Estrogen Receptor α, mitochondrial abundance and activity were maintained both in skeletal muscle and in liver. Our results reveal overlapping metabolic adaptations resulting from the overexpression of CYB5R3 and CR in females, but a specific crosstalk occurs when both interventions are combined, differing from the adaptations observed in TG males.