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The regulatory role of estrogen receptor beta (ERβ) and the JNK signaling pathway in the effect of high-dose boron on rat splenic lymphocytes has been examined by measuring proliferation, apoptosis, and immune function. The results showed that, compared with the control group, the addition of high-dose boron (40 mmol/L) reduced the proportion of CD3+, CD4+, and CD8+ T lymphocytes, the concentrations of IgG, IL-2, IFN-γ, and IL-4, the proliferation rate of splenic lymphocytes, and the expression levels of PCNA and Bcl-2 mRNA (P < 0.01 or P < 0.05), and increased the apoptosis rate of splenic lymphocytes, caspase-3, and BAX mRNA expression levels (P < 0.01 or P < 0.05). After specific blocking of ERβ, the addition of high-dose boron could not reduce the proportion of CD8+ T lymphocytes, the concentrations of IgG and cytokines IL-2, IFN-γ, and IL-4, the lymphocyte proliferation rate, or PCNA mRNA expression levels, nor could it increase BAX mRNA expression levels. After specific blocking of JNK, the addition of high-dose boron could not increase BAX mRNA expression levels. However, after specific blocking of ERβ and JNK, the addition of high-dose boron could neither reduce the proportion of CD4+ and CD8+ T lymphocytes, the concentrations of IgG and IL-2 (P > 0.05), nor increase caspase-3 and BAX mRNA expression levels (P < 0.01). The results suggest that the ERβ-mediated JNK signaling pathway participates in regulating the effects of high-dose boron on the expression of genes related to the proliferation and apoptosis of rat splenic lymphocytes. [ABSTRACT FROM AUTHOR]

Estrogen receptor α (ERα) promotes the growth and survival of ER‐positive breast cancer (BC) cells. ER regulates ER expression target genes by directly binding to specific estrogen response elements, upon activation by estrogens. In this study, 106 proteins interacting with endogenous chromatin‐bound ER in a BC cell line MCF7 were identified using the RIME method. The interactome data showed that the tripartite motif containing 28 (TRIM28) is the most significantly enriched ER‐associated protein. This study provides evidence that TRIM28 expression improves ER transcriptional activity and promotes the BC cells proliferation, migration, and invasion of BC cells. The high expression of TRIM28 is associated with poor clinical outcomes in patients with ER‐positive BC. Mechanistic experiments indicate that TRIM28 expression activates the AKT/GSK3β pathway. To conclude, TRIM28 acts as a regulatory protein of ER and AKT signaling; therefore, it can be a target for the therapeutic interventions of BC. [ABSTRACT FROM AUTHOR]

Polycystic ovarian syndrome (PCOS) is a prevalent endocrinological disorder affected by ghrelin. This study aimed to investigate the molecular mechanisms underlying the effects of ghrelin on PCOS manifestations in mice and to assess the therapeutic potential of ghrelin. Female C57BL/6 mice were subcutaneously injected with 6 mg/100 g dehydroepiandrosterone (DHEA) for 20 days to induce PCOS. Alterations in reproductive cycles, ovarian morphology, serum sex hormone levels, and related signaling markers were examined. Furthermore, ghrelin-induced effects on granulosa cells and the role of ghrelin/Gq/11/ Yes-associated protein (YAP) signaling were studied by silencing Gαq/11 or YAP using si-RNAs. Finally, we evaluated the therapeutic potential of anti-ghrelin antibodies in DHEA-induced PCOS mice. DHEA administration led to significant PCOS-associated changes including weight gain, disrupted estrous cycles, ovarian morphological alterations, and hormonal imbalances in mice, with elevated Gαq/11 and acylated ghrelin expression, which was also noted in PCOS patients. However, treatment with anti-ghrelin antibodies effectively managed DHEA-induced damage in PCOS mice. In vitro, ghrelin exposure resulted in granulosa cell injury and modulated estrogen receptors alpha (ERα) and YAP protein levels, whereas silencing YAP and Gαq/11 reversed ghrelin-induced detrimental effects and up-regulated ERα expression. This study revealed that DHEA-induced PCOS traits in mice could be improved by anti-ghrelin antibodies, with the ghrelin/Gq/11/YAP signaling pathway identified as a crucial mediator in granulosa cells, affecting ERα transcription to regulate PCOS. These findings suggest a potential therapeutic strategy for the treatment of PCOS. [ABSTRACT FROM AUTHOR]

For many diseases, including cancer, infections, and auto-immune diseases, the immune response is a major determinant of disease progression, response to therapy, and clinical outcome. Innate and adaptive immune responses are controlled by coordinated activity of different immune cell types. The functional activity state of immune cells is determined by Signal Transduction Pathways (STPs). A recently developed technology (Simultaneous Transcriptome-based Activity Profiling of Signal Transduction Pathways, STAP-STP) enables simultaneous and quantitative activity measurement of relevant STPs in immune cells based on mRNA-analysis. STAP-STP technology was used to analyze public transcriptome data of a variety of immune cell types in resting and activated functional state. In addition, a clinical study on rheumatoid arthritis (RA) was analyzed to illustrate utility of the technology. Per sample, activity of androgen and estrogen receptor, PI3K, MAPK, TGFβ, Notch, NFκB, JAK-STAT1/2, and JAK-STAT3 STPs was calculated, generating an STP activity profile (SAP) consisting of 9 activity scores. Each analyzed immune cell type, i.e. naive/resting and immune-activated CD4 + and CD8 + T cells, T helper cells, B cells, NK cells, monocytes, macrophages, and dendritic cells, had a reproducible and characteristic SAP, reflecting both cell type and its activity state. Analysis of clinical RA samples revealed increased TGFβ STP activity in whole blood samples. In conclusion, STAP-STP technology enables quantitative measurement of the functional activity state of immune cells of the innate and adaptive immune system. Aside from diagnostic applications, utility lies in unravelling abnormal immune function in disease and immunomodulatory drug development. [ABSTRACT FROM AUTHOR]

ER+/HER2- breast cancer is a common subtype of breast cancer. This study aimed to evaluate the prognostic value of ER-to-PR difference (EPD) in ER+/HER2- early breast cancer (EBC). A retrospective cohort study was conducted, including 3,340 ER+/HER2- EBC patients, divided into a training cohort of 2,873 patients and a validation cohort of 467 patients. The optimal EPD cutoff value for stratifying patients was determined using X-tile. Additionally, the prognostic value of EPD, when combined with other clinicopathological factors, was assessed using the Cox proportional hazards model and five traditional machine learning methods. The optimal cutoff value for EPD was determined as 10%, categorizing patients into EPD-low (ER-PR ≤ 10%) and EPD-high (ER-PR > 10%) expression groups. Patients with EPD-high tumors exhibited a poorer prognosis compared to those with EPD-low tumors. In the multivariate Cox model, EPD was identified as an independent prognostic factor for disease-free survival (DFS) (HR: 1.496, P = 0.004). Integrating EPD with clinicopathological parameters into a predictive model effectively predicts DFS in ER+/HER2- EBC patients. In the most effective CoxPH model, the area under the curve (AUC) values for predicting 3-year, 5-year, and 7-year DFS were 0.718, 0.702, and 0.701, respectively, in the WCH cohort, and 0.770, 0.739, and 0.743, respectively, in the FUSCC cohort. EPD may serve as a novel prognostic marker, allowing for the identification of a population with a poor prognosis in ER+/HER2- EBC, thereby aiding clinical decision-making. [ABSTRACT FROM AUTHOR]

Gonadal hormone activities mediated by androgen and estrogen receptors, along with cell-autonomous mechanisms arising from the absence of sex-chromosome dosage compensation, are key factors in avian sexual development. In this study, we generate androgen receptor (AR) knockout chickens (AR−/−) to explore the role of androgen signaling in avian sexual development. Despite developing sex-typical gonads and gonadal hormone production, AR−/− males and females are infertile. While few somatic sex-specific traits persist (body size, spurs, and tail feathers), crucial sexual attributes such as comb, wattles and sexual behaviors remain underdeveloped in both sexes. Testosterone treatment of young AR−/− males fails to induce crow behavior, comb development, or regression of the bursa of Fabricius, which are testosterone-dependent phenotypes. These findings highlight the significance of androgen receptor mechanisms in fertility and sex-specific traits in chickens, challenging the concept of a default sex in birds and emphasizing the dominance of androgen signaling in avian sexual development. The role of androgen signalling in avian sexual development is still unclear. This study generated androgen receptor knockout chickens and find that, despite developing typical gonads, the males and females are infertile and many sexual ornaments and behaviors remain underdeveloped in both sexes. [ABSTRACT FROM AUTHOR]

Introduction: All cosmetic ingredients must be evaluated for their safety to consumers. In the absence of in vivo data, systemic concentrations of ingredients can be predicted using Physiologically based Pharmacokinetic (PBPK) models. However, more examples are needed to demonstrate how they can be validated and applied in Next-Generation Risk Assessments (NGRA) of cosmetic ingredients. We used a bottom-up approach to develop human PBPK models for genistein and daidzein for a read-across NGRA, whereby genistein was the source chemical for the target chemical, daidzein. Methods: An oral rat PBPK model for genistein was built using PK-Sim® and in vitro ADME input data. This formed the basis of the daidzein oral rat PBPK model, for which chemical-specific input parameters were used. Rat PBPK models were then converted to human models using human-specific physiological parameters and human in vitro ADME data. In vitro skin metabolism and penetration data were used to build the dermal module to represent the major route of exposure to cosmetics. Results: The initial oral rat model for genistein was qualified since it predicted values within 2-fold of measured in vivo PK values. This was used to predict plasma concentrations from the in vivo NOAEL for genistein to set test concentrations in bioassays. Intrinsic hepatic clearance and unbound fractions in plasma were identified as sensitive parameters impacting the predicted Cmax values. Sensitivity and uncertainty analyses indicated the developed PBPK models had a moderate level of confidence. An important aspect of the development of the dermal module was the implementation of first-pass metabolism, which was extensive for both chemicals. The final human PBPK model for daidzein was used to convert the in vitro PoD of 33 nM (from an estrogen receptor transactivation assay) to an external dose of 0.2% in a body lotion formulation. Conclusion: PBPK models for genistein and daidzein were developed as a central component of an NGRA read-across case study. This will help to gain regulatory confidence in the use of PBPK models, especially for cosmetic ingredients. [ABSTRACT FROM AUTHOR]

Menopause weakens the brain's structural integrity and increases its susceptibility to a range of degenerative and mental illnesses. 17β estradiol (17βE2) exhibits potent neuroprotective properties. Exogenous estrogen supplementation provides neuroprotection, but the findings presented by the Million Women Study (MWS) and the Women's Health Initiative (WHI), as well as the increased risk of endometrial cancer, breast cancer and venous thromboembolism associated with estrogen use, have cast doubt on its clinical use for neurological disorders. Thus, the objective of our review article is to compile all in vitro and in vivo studies conducted till date demonstrating the neuroprotective potential of nonfeminizing estrogens. This objective has been achieved by gathering various research and review manuscripts from different records such as PubMed, Embase, Scopus, Google Scholar, Web of Science and OVID, using different terms like 'estrogen deficiency, 17β estradiol, non‐feminising estrogens, and brain disorder'. However, recent evidence has revealed the contribution of numerous non‐estrogen receptor‐dependent pathways in neuroprotective effects of estrogen. In conclusion, synthetic nonfeminizing estrogens that have little or no ER binding but are equally powerful (and in some cases more potent) in delivering neuroprotection are emerging as viable and potential alternatives. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGF) play important role in breast tumor growth, invasion, metastasis, patient survival and drug resistance. The aim of this study was to evaluate the protein expression status of EGFR and VEGF-A, as well as their association with hormone receptor status and histopathological characteristics in the invasive type of female breast cancer among Ethiopians. Method: The primary breast tumor tissues were obtained from 85 Ethiopian invasive breast cancer cases that underwent modified radical mastectomy (MRM) from June 2014 to June 2015. Their FFPE blocks were analyzed for EGFR and VEGF protein expressions using immunohistochemical techniques. The expressions were also correlated with histopathologic features. Result: Epidermal growth factor receptor over-expression was observed in 22% of the tumor samples. VEGF-A expression was negative in 13.41%, low in 63.41%, moderate in 20.73%, and high in 2.44%. EGFR expression, but not VEGF-A, showed a significant inverse correlation with both estrogen receptor (ER) (P = 0.01) and progesterone receptor (PR) statuses (P = 0.04). EGFR and VEGF expressions did not show significant association with tumor size, grade, lymph node status or age at diagnosis. Conclusion: Epidermal growth factor receptor expression was most likely associated with ER and PR negative tumors. Assessments of multiple molecular markers aid to understand the biological behavior of the disease in Ethiopian population. It might also help to predict which group of patients might get more benefit from the selected treatment strategies and which are not. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, one of the most often diagnosed malignancies worldwide, continues to take countless women's lives. Its treatment usually involves targeting the human estrogen receptor alpha (ERα). Current research explores the potential of natural compounds to regulate ERα activity, providing a hopeful direction for breast cancer therapy. Our study utilized a comprehensive approach to identify promising natural compounds for breast cancer treatment, including quantum descriptors, molecular docking, molecular dynamics simulations, and ADMET/pharmacokinetics analysis. Results: Six natural compounds derived from podophyllum medicinal plants, namely 4-demethylpodophyllotoxin (NP1), α-peltatin (NP2), podophyllotoxin (NP3), deoxypodophyllotoxin (NP4), podophyllotoxone (NP5), and β-peltatin (NP6), were investigated as potential selective estrogen receptor α (ERα) inhibiting agents for breast cancer. These compounds demonstrated the strongest binding affinity to the target enzyme, with binding energies of − 8.9 and − 8.1 kcal/mol, respectively. Further assessments of drug-likeness and ADME properties were conducted for these compounds, along with quantum calculations (HOMO–LUMO) to evaluate their reactivity. Additionally, molecular dynamics studies were performed to assess the stability of the NP1 and NP2 protein–ligand complexes. Conclusions: We analyzed six natural compounds comprehensively, evaluating their ADME properties, molecular docking interactions, quantum descriptors, and dynamic simulations. Our findings demonstrate that these natural compounds are promising possibilities for treating breast cancer. Additionally, they may provide a basis for developing future compounds targeting estrogen receptor α (ERα) activity. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion 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. [ABSTRACT FROM AUTHOR]

Divergent trends of breast cancer incidence by subtype have been reported in the United States and elsewhere; however, it remains unknown whether this trend has continued until the era of the COVID‐19 pandemic. Using high‐quality population‐based cancer registry data, representing 83% of the US population, this study examined breast cancer incidence rates by estrogen receptor (ER) status in women aged 20–84 years from 2004 to 2020. The incidence rate of ER‐positive cancer increased by 1.75% per year from 2004 to 2009 (95% confidence interval [CI] = 1.26%–3.15%) and has slowed to a 0.87% annual increase (95% CI = 0.41%–1.03%) from 2009 to 2019, followed by a 10.2% reduction from 2019 to 2020. Trends were generally similar across race and ethnicity, although young women (20–49 years), Asian or Pacific Islander, and Hispanic women experienced steady increases until 2019. The incidence rate of ER‐negative cancer decreased by 3.13% annually (95% CI = −4.2% to −2.55%) from 2004 to 2012, and the decrease stabilized from 2012 to 2019 (annual percent change: 0.55%; 95% CI = −1.30% to 0.92%), followed by a 6.0% reduction from 2019 to 2020, with trends generally consistent by age and across racial and ethnic groups. The stabilization of the steep decline in ER‐negative cancer suggests a departure from the encouraging trajectories projected in earlier studies. Coupled with the deceleration in the rise of ER‐positive cancer, the latest trend signals a potential stabilization in the previous rise of the proportional burden of ER‐positive cancer. Understanding the impact of the pandemic on each subtype of breast cancer individually may provide a more comprehensive insight into its long‐term sequelae on survival and mortality. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to investigate whether estrogen receptor (ER) status affects the predictive role of the human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) score on the efficacy of neoadjuvant treatment for HER2‐positive breast cancer. Methods: This retrospective study comprised 167 individuals diagnosed with HER2‐positive invasive breast cancer who had undergone neoadjuvant treatment and surgery. Uni‐ and multivariable logistic regression analyses were performed on the relationship between the HER2 IHC score and total pathological complete response (tpCR), breast pathological complete response (bpCR), or axillary partial response (apCR). Subgroup analyses were used to investigate whether the relationship between the HER2 IHC score and tpCR, bpCR, or apCR differed by ER or PR status. Results: The overall tpCR rate for HER2‐positive breast cancers treated with neoadjuvant treatment was 41.32% (69 of 167). The tpCR, bpCR, and apCR rates were greater in the HER2 IHC 3+ group (tpCR: IHC 3 + 47.69% vs. IHC 2 + 18.92%, p = 0.009). Significant interactions between HER2 IHC score and tpCR or bpCR were found in subgroup analyses based on ER status (tpCR: p for interaction = 0.001; bpCR: p for interaction = 0.001). Among ER‐positive patients, the HER2 IHC 2+ group had substantially decreased tpCR, bpCR, and apCR rates than the HER2 IHC 3+ group (tpCR rate: p = 0.003; bpCR rate: p = 0.002; apCR rate: p = 0.002). For ER‐negative individuals, the tpCR, bpCR, and apCR rates did not differ significantly among the HER2 IHC 3+ versus HER2 IHC 2+ groups. Similarly, interactions between HER2 IHC score and tpCR, bpCR, or apCR were found in subgroup analyses based on PR status. Conclusion: HER2 IHC 2+ may indicate a decreased tpCR rate, bpCR rate, and apCR rate to neoadjuvant treatment in HR‐positive patients having HER2‐positive breast cancer, but not in HR‐negative patients. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) accounts for 24.2% of all women's malignant tumors, with rising survival rates due to advancements in chemotherapy and targeted treatments. However, second primary cancers, particularly lung cancer (LC), have become more prevalent, often emerging approximately 10 years after BC treatment. This study presents a case series of 9 women diagnosed with second primary LC following BC, treated at a high-complexity hospital in Colombia between 2014 and 2019. All initial BCs were ductal carcinomas, 7 were triple negative, 1 was human epidermal growth factor receptor 2 positive, and 1 was estrogen and progesterone positive. Each patient had undergone radiation therapy, and 7 had received chemotherapy, increasing their LC risk. The second primary LCs, all adenocarcinomas, were confirmed using immunohistochemical stains for thyroid transcription factor-1 (TTF-1), Napsin A, and estrogen receptor (ER) status. The interval between treatments and LC detection ranged from 1 to 17 years, with 4 cases identified after 10 years and 3 within 1 to 3 years, underscoring the need for prolonged surveillance. Seven LCs were ipsilateral to the BC and radiation site, while 2 were contralateral, highlighting the necessity of monitoring both sides for potential LC development. This case series enhances the local epidemiological understanding, showing that prior radiotherapy for BC and histological analysis are key in characterizing second primary LC patients. The study emphasizes the critical role of accurate histological diagnosis in guiding treatment approaches for lung lesions in BC survivors. [ABSTRACT FROM AUTHOR]

Estrogen receptor alpha (ERα) plays a critical role in breast cancer (BC) progression, with endocrine therapy being a key treatment for ERα + BC. However, resistance often arises due to somatic mutations in the ERα ligand-binding domain (LBD). Lasofoxifene, a third-generation selective estrogen receptor modulator, has shown promise against Y537S and D538G mutations. However, the emergence of a novel F404 mutation in patients with pre-existing LBD mutations raises concerns about its impact on lasofoxifene efficacy. This study investigates the impact of the dual Y537S and F404V mutations on lasofoxifene's efficacy. Using molecular dynamics simulations and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) free energy calculations, we found that the dual mutation reduces lasofoxifene binding affinity and binding free energy, disrupts crucial protein-ligand interactions, and induces significant conformational changes in the ligand-binding pocket. These alterations are likely due to the loss of the pi-pi stacking interaction in the F404V mutation. These findings suggest a potential reduction in lasofoxifene efficacy due to the dual mutation. Further experimental validation is required to confirm these results and fully understand the impact of dual mutations on lasofoxifene's effectiveness in ERα + metastatic BC. [ABSTRACT FROM AUTHOR]

Background: Monocytes 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. Methods: To 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. Results: When 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. Conclusions: This study identified classical monocytes to be associated with ER positive BC and with patient response to neoadjuvant endocrine treatment and cancer vaccination. [ABSTRACT FROM AUTHOR]

Nine new coumarin derivatives of 2‐(7‐hydroxy‐2‐oxo‐2H‐chromen‐4‐yl)acetic acid 6a–i have been successfully synthesized through amide coupling with various substituted anilines and 2‐aminopyridines. The synthesized derivatives were screened for anticancer activity using MTT assay on MCF‐7 cell line. The results showed that compound 6b inhibited MCF‐7 cell growth in a dose‐dependent manner and reached 47% inhibition at 40 µM, being better than starting material 5 and references 3 and 5FU drug. Moreover, 6b inhibited significantly 3D tumorsphere formation. The para‐Br substitution of 6b seems to be important for activity. Docking study suggests estrogen receptor and/or 3a‐HSD type 3 protein could be the target(s) for anticancer activity of this class of compounds. Further optimization of compound 6b should lead to more potent compound. [ABSTRACT FROM AUTHOR]

Objective: This study aims to examine the expression of androgen receptor (AR) and estrogen receptor (ER) in patients with classic Kaposi's sarcoma (CKS) in Xinjiang, as well as to assess the serum levels of sex hormones in these patients. The objective is to explore potential new directions and targets for diagnosing and treating CKS in Xinjiang. Methods: The case group comprised 35 patients diagnosed with CKS who presented at our hospital from 2014 to 2021. The control group consisted of 35 patients with pyogenic granuloma (PG) who visited the hospital during the same period, selected using propensity score matching (PSM). Immunohistochemistry was used to detect AR, human herpesvirus type 8 (HHV‐8), and ER in paraffin‐embedded tissue samples from patients diagnosed with CKS and PG. Additionally, enzyme‐linked immunosorbent assay (ELISA) was used to quantitatively measure serum sex hormone levels in the 35 patients with CKS and 35 patients with PG. Results: AR expression was relatively weak in both the CKS and PG groups, with the PG group exhibiting a slightly stronger expression than the CKS group. Conversely, the expression of ER was significantly higher in the CKS group compared to the PG group (p < 0.05). Additionally, serum testosterone (T) levels were elevated in the CKS group, while serum estradiol (E2) levels were higher in the PG group (p < 0.05). Conclusion: Sex hormones and their receptors are implicated in the pathogenesis of CKS in Xinjiang. The use of ER antagonists may represent a novel avenue for research and treatment of CKS. [ABSTRACT FROM AUTHOR]

Background: The targeted therapy using breast cancer (BC)-associated biomarkers has significantly minimized the side-effects of BC treatment. This study aims to elucidate the role of Nectin2, NUF2, and Nectin4 gene expression in the pathogenesis of BC. Method: In this case-control study, the expression of Nectin2, Nectin4, and NUF2 genes was investigated through real-time polymerase chain reaction assay in 46 tumor tissues from BC patients and 46 adjacent non-tumorous tissues as a control group. Data were analyzed using SPSS-21 software, employing independent t-tests and oneway ANOVA. A P-value of <0.05 was considered statistically significant. Results: The results demonstrated a significant increase in the expression of the NUF2 gene in tumor tissues compared with adjacent normal tissues (P = 0.005, fold change = 3.7). No statistically significant difference was observed in the expression of Nectin2 and Nectin4 between the tumor and adjacent tissues. However, higher expression of Nectin2 was noted in the early stages of the disease, particularly in subtypes with estrogen receptor-positive (ER+), progesterone receptor positive (PR+), and human epidermal growth factor receptor 2 negative (HER2-). Furthermore, the expression of NUF2 and Nectin4 was elevated in advanced stages and triple-negative BC subtypes. Notably, the expression of these three genes was higher in patients aged ≤ 45 years. Conclusion: The findings suggest that the expression levels of NUF2, Nectin2, and Nectin4 genes may influence the initiation, progression, and pathogenesis of BC subtypes. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a leading cause of cancer-related mortality in women, with a rising incidence globally. Neoadjuvant chemotherapy(NACT) is a standard treatment approach for operable advanced loco-regional breast cancer, aiming to achieve tumor shrinkage, downstaging, and improved surgical outcomes. GATA3 expression has been identified as a significant marker for tumor differentiation, estrogen receptor status, and clinical outcomes in breast cancer. Objectives: To investigate the expression of GATA3 in post-NACT breast carcinoma cases and its utility in confirming histopathological diagnosis of partial and complete response, thereby guiding treatment strategies and predicting patient outcomes. Methods: A cross-sectional study of 60 breast carcinoma cases treated with NACT was conducted at Mysore Medical College and Research Institute. GATA3 expression was evaluated using immunohistochemistry, and its correlation with histopathological response to chemotherapy was assessed. Results: Among 60 cases, GATA3 was expressed in 87% of cases, with 91% of partial responders and 73% of complete responders showing immunopositivity. The study demonstrates GATA3 expression in post-NACT breast carcinoma cases, highlighting its potential as a predictive marker for treatment outcomes. Conclusion: GATA3 is a valuable marker for predicting response to NACT in breast cancer patients, supporting its utility in confirming histopathological diagnosis, guiding treatment strategies, and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer characterized by the absence of estrogen and progesterone receptors and HER2 expression, leading to limited treatment options and a poorer prognosis. TNBC is particularly prevalent in premenopausal African-descent women and is associated with aggressive tumor behavior and higher metastatic potential. Tumor-associated macrophages (TAMs) are abundantly present within the TNBC microenvironment and play pivotal roles in promoting tumor growth, progression, and metastasis through various mechanisms, including immune suppression and enhancement of angiogenesis. This review provides an in-depth overview of TNBC, focusing on its epidemiology, its molecular characteristics, and the critical influence of TAMs. It discusses the pathological and molecular aspects that define TNBC's aggressive nature and reviews current and emerging therapeutic strategies aimed at targeting these dynamics. Special attention is given to the role of TAMs, exploring their potential as therapeutic targets due to their significant impact on tumor behavior and patient outcomes. This review aims to highlight the complexities of the TNBC landscape and to present the innovative approaches that are currently being pursued to improve therapeutic efficacy and patient survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has changed the way we treat triple-negative breast cancer (TNBC), a type of breast cancer that does not have common markers like estrogen, progesterone, or HER2. TNBC has the worst outlook among breast cancers, but it may respond better to immunotherapy because it often shows higher levels of PD-L1 and has more immune cells attacking the tumor. Recently, the FDA approved pembrolizumab (Keytruda) combined with chemotherapy for advanced TNBC, offering new hope for patients. However, not all patients respond equally well, mainly because not everyone has high PD-L1 levels. To improve treatment success, combining immunotherapy with other treatments like chemotherapy, targeted therapies, or radiation seems promising. This review explains TNBC and immunotherapy, discusses current and future combination treatment strategies, and explores the challenges and potential new approaches that might soon be available for treating TNBC. Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), human epidermal growth factor receptor 2 (HER2), and progesterone receptors (PRs). TNBC has the poorest prognosis among breast cancer subtypes and is more likely to respond to immunotherapy due to its higher expression of PD-L1 and a greater percentage of tumor-infiltrating lymphocytes. Immunotherapy has revolutionized TNBC treatment, especially with the FDA's approval of pembrolizumab (Keytruda) combined with chemotherapy for advanced cases, opening new avenues for treating this deadly disease. Although immunotherapy can significantly improve patient outcomes in a subset of patients, achieving the desired response rate for all remains an unmet clinical goal. Strategies that enhance responses to immune checkpoint blockade, including combining immunotherapy with chemotherapy, molecularly targeted therapy, or radiotherapy, may improve response rates and clinical outcomes. In this review, we provide a short background on TNBC and immunotherapy and explore the different types of immunotherapy strategies that are currently being evaluated in TNBC. Additionally, we review why combination strategies may be beneficial, provide an overview of the combination strategies, and discuss the novel immunotherapeutic opportunities that may be approved in the near future for TNBC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age‐related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta‐analysis of 335,803 single‐nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex‐dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex‐biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex‐stratified analysis of normal vascular aging revealed that angiogenesis and various stress‐response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD. [ABSTRACT FROM AUTHOR]

Cancers develop resistance to inhibitors of oncogenes mainly due to target-centric mechanisms such as mutations and splicing. While inhibitors or antagonists force targets to unnatural conformation contributing to protein instability and resistance, activating tumor suppressors may maintain the protein in an agonistic conformation to elicit sustainable growth inhibition. Due to the lack of tumor suppressor agonists, this hypothesis and the mechanisms underlying resistance are not understood. In estrogen receptor (ER)-positive breast cancer (BC), androgen receptor (AR) is a druggable tumor suppressor offering a promising avenue for this investigation. Spatial genomics suggests that the molecular portrait of AR-expressing BC cells in tumor microenvironment corresponds to better overall patient survival, clinically confirming AR's role as a tumor suppressor. Ligand activation of AR in ER-positive BC xenografts reprograms cistromes, inhibits oncogenic pathways, and promotes cellular elasticity toward a more differentiated state. Sustained AR activation results in cistrome rearrangement toward transcription factor PROP paired-like homeobox 1, transformation of AR into oncogene, and activation of the Janus kinase/signal transducer (JAK/STAT) pathway, all culminating in lineage plasticity to an aggressive resistant subtype. While the molecular profile of AR agonist-sensitive tumors corresponds to better patient survival, the profile represented in the resistant phenotype corresponds to shorter survival. Inhibition of activated oncogenes in resistant tumors reduces growth and resensitizes them to AR agonists. These findings indicate that persistent activation of a context-dependent tumor suppressor may lead to resistance through lineage plasticity-driven tumor metamorphosis. Our work provides a framework to explore the above phenomenon across multiple cancer types and underscores the importance of factoring sensitization of tumor suppressor targets while developing agonist-like drugs. [ABSTRACT FROM AUTHOR]

Garcinia kola is a medicinal food commonly consumed in Sub-Sahara Africa, for which Kolaviron (KV) is the active portion. As a follow-up to our earlier chemopreventive studies, we investigated the chemotherapeutic effects of KV on experimentally induced mammary carcinogenesis in female Wistar rats. Mammary carcinogenesis was induced using 80 mg/kg of 7,12-dimethylbenzanthracene (DMBA) administered by oral gavage. One hundred-fifty days post-DMBA induction, estrogen receptor-α (ER-α) levels were determined in the experimental rats before treatment with KV commenced. Treatment was done using 50, 100, and 200 mg/kg KV thrice a week for 4 weeks, after which the experiment was terminated. Significantly higher levels of estrogen receptor-α, CYP 1A1, malondialdehyde, formation of lobular neoplastic cells, epithelial hyperplasia, lymphocyte infiltration, and increased cytokine (interleukin-6 and tumor necrosis factor-α) activity were observed in DMBA-induced rats, which were attenuated in KV-treated rats. Tyrosine metabolism was exclusively enriched in DMBA-induced rats in contrast to KV-treated rats. Collectively, the results point to the chemotherapeutic potential of KV. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer is the eighth most common cause of cancer-related deaths worldwide. There are two main histological subtypes of esophageal cancer: adenocarcinoma and squamous cell carcinoma. Among the factors associated with the development of esophageal cancer, estrogen receptor beta (ERβ) has been found to have a clinical significance. Aim: To investigate the relationship between ERβ expression and esophageal cancer. Methods: English Medical literature searches were conducted for ERβ expression in patients with esophageal cancer versus healthy controls. Searches were performed up to August 31, 2023, using MEDLINE, PubMed, Embase and Google Scholar. Meta-analysis was performed by using Comprehensive meta-analysis software (Version 4, Biostat Inc., Englewood, NJ, USA). Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated. Heterogeneity was evaluated using Cochrane Q-test, and it was considered present if the Q-test P value was less than 0.10. I2 statistic was used to measure the proportion of inconsistency in individual studies, with I2 > 50% representing heterogeneity. We also calculated a potential publication bias. Results: Ten studies representing 11 substudies were selected according to the inclusion criteria. The odds ratio of ERβ expression in fixed effect analysis was 0.448, 95% CI: 0.237 to 0.846, 55.2% lower in esophageal cancer than in normal mucosa. Heterogeneity and inconsistency were low, and no publication bias was demonstrated. Conclusion: This meta-analysis showed that ERβ expression is lower in esophageal cancer biopsy specimens than in healthy controls, this finding may have a significant effect on survival and can lead to new therapeutic avenues. [ABSTRACT FROM AUTHOR]

Purpose: To verify the ability of pretreatment [18F]FDG PET/CT and T1-weighed dynamic contrast-enhanced MRI to predict pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients. Methods: This retrospective study includes patients with BC of no special type submitted to baseline [18F]FDG PET/CT, NAC and surgery. [18F]FDG PET-based features reflecting intensity and heterogeneity of tracer uptake were extracted from the primary BC and suspicious axillary lymph nodes (ALN), for comparative analysis related to NAC response (pCR vs. non-pCR). Multivariate logistic regression was performed for response prediction combining the breast tumor-extracted PET-based features and clinicopathological features. A subanalysis was performed in a patients' subsample by adding breast tumor-extracted first-order MRI-based features to the multivariate logistic regression. Results: A total of 170 tumors from 168 patients were included. pCR was observed in 60/170 tumors (20/107 luminal B-like, 25/45 triple-negative and 15/18 HER2-enriched surrogate molecular subtypes). Higher intensity and higher heterogeneity of [18F]FDG uptake in the primary BC were associated with NAC response in HER2-negative tumors (immunohistochemistry score 0, 1 + or 2 + non-amplified by in situ hybridization). Also, higher intensity of tracer uptake was observed in ALN in the pCR group among HER2-negative tumors. No [18F]FDG PET-based features were associated with pCR in the other subgroup analyses. A subsample of 103 tumors was also submitted to extraction of MRI-based features. When combined with clinicopathological features, neither [18F]FDG PET nor MRI-based features had additional value for pCR prediction. The only significant predictors were estrogen receptor status, HER2 expression and grade. Conclusion: Pretreatment [18F]FDG PET-based features from primary BC and ALN are not associated with response to NAC, except in HER2-negative tumors. As compared with pathological features, no breast tumor-extracted PET or MRI-based feature improved response prediction. [ABSTRACT FROM AUTHOR]

Overexpression of HER2/neu and estrogen receptors (ER) and/or progesterone receptors (PR) are reported to be inversely associated with breast cancer (BC). The relationship between hormone receptors and HER2/neu is attenuated by age and numerous other clinical factors. Here, we examined the link between hormone receptors and HER-2/neu in terms of an additional variable, such as the histological grades of breast tumors in women. A total of 240 breast cancer samples were obtained from the Department of Histopathology at the University of Lahore Teaching Hospital in Lahore, Punjab. Immunohistochemistry (IHC) was used to examine the expression of hormone receptors and HER-2/neu. Using the χ2 and fisher exact test, the association between hormone receptors and HER-2/neu in various age groups and histological grades was investigated. Patients that were included in this study had ages between 30 and 90 years, with a mean age of 51.89 ± 12.01 years, and were mostly having grade 1 tumors. The most prevalent type of breast cancer was invasive ductal carcinoma (95.83%). It was found that the ER, PR, and HER-2/neu were more expressive in older (above 45) and grade 1 tumors as compared to younger (≤45) and higher-grade tumor patients. HER-2 was negatively correlated with hormonal receptors in women aged >45 years old with grade-1 tumors. Hormonal receptor (ER/PR) expression is asso)ciated with HER-2/neu expression not only in older age (>45) but also in grade 1 tumors. This correlation between HER2/neu and hormone receptors that improves with age and tumor grade is useful for predicting outcomes and, likely, for guiding therapy choices. [ABSTRACT FROM AUTHOR]

Rationale: Evidence of the effects of chronic caffeine (CAFF)-containing beverages, alone or in combination with agomelatine (AGO) or quetiapine (QUET), on electroencephalography (EEG), which is relevant to cognition, epileptogenesis, and ovarian function, remains lacking. Estrogenic, adenosinergic, and melatonergic signaling is possibly linked to the dynamics of these substances. Objectives: The brain and ovarian effects of CAFF were compared with those of AGO + CAFF and QUET + CAFF. The implications of estrogenic, adenosinergic, and melatonergic signaling and the brain-ovarian crosstalk were investigated. Methods: Adult female rats were administered AGO (10 mg/kg), QUET (10 mg/kg), CAFF, AGO + CAFF, or QUET + CAFF, once daily for 8 weeks. EEG, estrous cycle progression, and microstructure of the brain and ovaries were examined. Brain and ovarian 17β-estradiol (E2), antimullerian hormone (AMH), estrogen receptor alpha (E2Rα), adenosine receptor 2A (A2AR), and melatonin receptor 2 (MT2R) were assessed. Results: CAFF, alone or combined with AGO or QUET, reduced the maximum EEG peak, which was positively linked to ovarian E2Rα, negatively correlated to cortical neurodegeneration and ovarian MT2R, and associated with cystic ovaries. A large corpus luteum emerged with AGO + CAFF and QUET + CAFF, antagonizing the CAFF-mediated increased ovarian A2AR and reduced cortical E2Rα. AGO + CAFF provoked TTP delay and increased ovarian AMH, while QUET + CAFF slowed source EEG frequency to δ range and increased brain E2. Conclusions: CAFF treatment triggered brain and ovarian derangements partially antagonized with concurrent AGO or QUET administration but with no overt affection of estrus cycle progression. Estrogenic, adenosinergic, and melatonergic signaling and brain-ovarian crosstalk may explain these effects. [ABSTRACT FROM AUTHOR]

Cystatin SN (CST1) appears to have pro-tumor effects in breast cancer (BC) and is involved in ferroptosis; however, there is no report on the regulation of ferroptosis by CST1 for BC development. The purpose of this study is to investigate the functions and mechanisms operated by CST1 in BC development and ferroptosis. Transcription Factor Activator Protein 2γ (TFAP2C) and CST1 levels in BC tissues and estrogen receptor (ER)+ cells were quantified by RT-qPCR and western blotting. After knocking down TFAP2C and CST1 expression in MCF7 and T47D cells, the proliferation, colony formation ability, apoptosis, and cell cycle were assessed. Ferroptosis was verified by detecting glutathione peroxidase 4 (GPX4) and 4-hydroxy-2-nonenal (4HNE) levels. The kits were used to test Fe2+, reactive oxygen species, malondialdehyde, and glutathione levels, and ultrastructure of mitochondria was observed through transmission electron microscope. Dual-luciferase reporter assay and chromatin immunoprecipitation test were carried out to investigate the interaction of TFAP2C and CST1. A transplanted tumor model was established to explore the function of TFAP2C in tumorigenesis by quantifying TFAP2C, CST1, Ki67, and GPX4 levels through western blotting and immunochemistry after silencing TFAP2C. TFAP2C and CST1 were predominantly expressed in BC cells. Silencing of TFAP2C or CST1 expression suppressed ER+ BC cell proliferation, promoted apoptosis and ferroptosis, and blocked cell cycle transition from G1 phase to S phase. TFAP2C knockdown in transplanted tumors inhibited tumor growth and GPX4 level. Upregulating CST1 nullified the anti-tumor effects of TFAP2C knockdown and TFAP2C promoted CST1 expression through transcription activation. TFAP2C activates CST1 transcription to facilitate BC development and block ferroptosis. [ABSTRACT FROM AUTHOR]

Objective: The aim of this retrospective study was to analyze the predictive capabilities of preoperative mammography, dynamic contrast-enhancedmagnetic resonance imaging (DCE-MRI), and diffusion-weighted imaging (DWI) in determining hormone receptor (HRc) status for pure ductal carcinoma in situ (DCIS) lesions. Materials and Methods: The study included a total of 79 patients who underwent preoperative mammography (MG) and MRI between December 2018 and December 2023 and were subsequently diagnosed with pure DCIS after surgery. The correlation between MG, DCE-MRI, and DWI features and estrogen receptor (ER) and progesterone receptor (PR) status was examined. Results: Among the lesions, 44 were double HRc-positive (ER and PR-positive), 13 were single HRc-positive (ER-positive and PR-negative or ERnegative and PR-positive) and 22 were double HRc-negative (ER and PR-negative). The presence of symptom (p = 0.029), the presence of comedo necrosis (p = 0.005) and high histological grade (p<0.001) were found to be associated with ER and PR negativity. Amorphous microcalcifications were more commonly observed in the double HRc-negative group, while linear calcifications were more prevalent in both double and single HRc-positive groups (p = 0.020). Non-mass enhancement (NME) with a linear distribution was significantly more common in double HRc-negative lesions (38%), and NME with a segmental distribution in both double (43%) and single (50%) receptor-positive lesions (p = 0.042). Evaluation of DWI findings revealed that a higher lesion-to-normal breast parenchyma apparent diffusion coefficient (ADC) ratio statistically increased the probability of HRc positivity (p = 0.033). Conclusion: Certain clinicopathological, mammography, and MRI features, along with the lesion-to-normal breast parenchyma ADC ratio, can serve as predictors for HRc status in DCIS lesions. [ABSTRACT FROM AUTHOR]

Context.--Metastatic pleomorphic lobular carcinoma (MPLC) to the bladder is rare and has considerable histologic and immunohistochemical overlap with plasmacytoid urothelial carcinoma (PUC). Objective.--To distinguish MPLC from PUC morphologically and immunohistochemically, including a newer marker, TRPS1. Design.--Ten MPLCs to the bladder were reassessed and stained with estrogen, progesterone, and androgen receptors; GATA3; keratin 5/6; HMWK; GCDFP-15; and TRPS1. Sixteen PUCs constituted controls. Results.--We studied 4 transurethral resections of bladder tumors and 6 biopsies from 10 women (median age, 69 years) who had breast cancer on average 15 years prior. Microscopic patterns included single cells and cords of cells (n = 4), nests/sheets of dyscohesive cells (n = 2), or both (n = 4). All tumors had cells with voluminous eosinophilic cytoplasm and eccentric nuclei mimicking PUC, and 7 of 10 tumors had signet ring cells. MPLCs were positive for estrogen (8 of 10), progesterone (3 of 7), and androgen (4 of 10) receptors; GCDFP-15 (7 of 10); GATA3 (9 of 10); HMWK (7 of 8); and TRPS1 (7 of 10). No MPLCs stained for keratin 5/6 (n = 9). Of 16 PUCs, 2 showed faint and 2 demonstrated strong TRSP1 staining; 7 of 16 were negative for p63. Conclusions.--MPLC to bladder often presents in patients with a remote history of breast cancer, exhibiting significant histologic and immunohistochemical overlap with PUC. Based on prior works and the current study, estrogen receptor (particularly SP-1), mammaglobin, and p63 help differentiate MPLC from PUC. Keratin 5/6 may aid in distinguishing a less frequent basal-type PUC because it is typically negative in MPLC. Some PUCs express TRPS1. Caution should be exercised because immunophenotypes of these tumors greatly overlap, and ramifications of misclassification are major. [ABSTRACT FROM AUTHOR]

Context.--Biomarker reporting has increasingly become a key component of pathology reporting, providing diagnostic, prognostic, and actionable therapeutic data for patient care. Objective.--To expand and improve the College of American Pathologists (CAP) biomarker protocols. Design.--We surveyed CAP members to better understand the limitations they experienced when reporting cancer biomarker results. A Biomarker Workgroup reviewed the survey results and developed a strategy to improve and standardize biomarker reporting. Drafts of new and revised bio-marker protocols were reviewed in both print and electronic template formats during interactive webinars presented to the CAP House of Delegates. Feedback was collected, and appropriate revisions were made to finalize the protocols. Results.--The first phase of the CAP Biomarker Workgroup saw the development of (1) a new stand-alone general Immunohistochemistry Biomarker Protocol that includes reporting for ER (estrogen receptor), PR (progesterone receptor), Ki-67, HER2 (human epidermal growth factor receptor 2), PD-L1 (programmed death ligand-1), and mismatch repair; (2) a new Head and Neck Biomarker Protocol that updates the prior 2017 paper-only version into an electronic template, adding new diagnostic and theranostic markers; (3) a major revision to the Lung Biomarker Protocol to streamline it and add in pan-cancer markers; and (4) a revision to the Colon and Rectum Biomarker Protocol to add HER2 reporting. Conclusions.--We have taken a multipronged approach to improving biomarker reporting in the CAP cancer protocols. We continue to review current biomarker reporting protocols to reduce and eliminate unnecessary methodo-logic details and update with new markers as needed. The biomarker templates will serve as standardized modular units that can be inserted into cancer-reporting protocols. [ABSTRACT FROM AUTHOR]

To assess the risk stratification of clinicopathologically and molecularly classified endometrial cancer based on estrogen receptor (ER) and L1 cell adhesion molecule (L1CAM) expression. This was a retrospective study of patients who underwent primary treatment at a single tertiary center. Carcinomas were classified into 5 clinicopathological risk groups, as per European guidelines. Immunohistochemistry and polymerase-ϵ sequencing were conducted for molecular classification and determination of ER and L1CAM expression. Data from 1044 patients were analyzed. The median follow-up was 67.5 months. In univariable analyses, ER expression correlated with improved disease-specific survival (DSS) in the "no specific molecular profile" (NSMP) (P < 0.001) and mismatch repair deficient (MMRd) (P = 0.002) subgroups. Negative L1CAM expression was associated with enhanced DSS in the NSMP subgroup alone (P < 0.001). ER (hazard ratio [HR] 0.18), but not L1CAM, exhibited prognostic significance within NSMP when controlling for parameters available at the time of diagnosis (tumor histotype, grade, age). ER and L1CAM were not independently associated with DSS within NSMP when controlling for parameters available after surgery (clinicopathological risk groups, age, adjuvant therapy). However, in high-risk–advanced-metastatic cases, both ER (HR 0.26) and L1CAM (HR 3.9) independently correlated with DSS. Similarly, within MMRd, ER was associated with improved DSS in high-risk–advanced-metastatic carcinomas (HR 0.42). The prognostic significance of ER and L1CAM varies across clinicopathological risk groups and molecular subgroups of endometrial cancer. Notably, risk assessment for high-risk–advanced-metastatic NSMP and MMRd subtype carcinomas can be refined by ER status. • ER independently linked to disease-specific survival in high-risk–advanced-metastatic NSMP and MMRd carcinomas. • The independent prognostic value of L1CAM limited to high-risk–advanced-metastatic NSMP carcinomas. • ER and L1CAM association with low grade hinders their prognostic enhancement for low-risk carcinomas. • Novel methods are essential to refine prognosis assessment especially in intermediate risk categories. [ABSTRACT FROM AUTHOR]

Plastic material versatility has resulted in a substantial increase in its use in several sectors of our everyday lives. Consequently, concern regarding human exposure to nano-plastics (NPs) and micro-plastics (MPs) has recently increased. It has been shown that plastic particles entering the bloodstream may adhere to the erythrocyte surface and exert adverse effects following erythrocyte aggregation and adhesion to blood vessels. Here, we explored the effects of polystyrene nano-plastics (PS-NPs) and micro-plastics (PS-MPs) on human erythrocytes. Cellular morphology, binding/internalization of PS-NPs and PS-MPs, oxidative stress parameters, as well as the distribution and anion exchange capability of band 3 (anion exchanger 1; SLC4A1) have been analyzed in human erythrocytes exposed to 1 μg/mL PS-NPs or PS-MPs for 3 and 24 h, respectively. The data obtained showed significant modifications of the cellular shape after exposure to PS-NPs or PS-MPs. In particular, a significantly increased number of acanthocytes, echinocytes and leptocytes were detected. However, the percentage of eryptotic cells (<1 %) was comparable to physiological conditions. Analytical cytology and confocal microscopy showed that PS-NPs and PS-MPs bound to the erythrocyte plasma membrane, co-localized with estrogen receptors (Erα/ERβ), and were internalized. An increased trafficking from the cytosol to the erythrocyte plasma membrane and abnormal distribution of ERs were also observed, consistent with ERα-mediated binding and internalization of PS-NPs. An increased phosphorylation of ERK1/2 and AKT kinases indicated that an activation of the ER-modulated non-genomic pathway occurred following exposure to PS-NPs and PS-MPs. Interestingly, PS-NPs or PS-MPs caused a significant production of reactive oxygen species, resulting in an increased lipid peroxidation and protein sulfhydryl group oxidation. Oxidative stress was also associated with an altered band 3 ion transport activity and increased oxidized haemoglobin, which led to abnormal clustering of band 3 on the plasma membrane. Taken together, these findings identify cellular events following the internalization of PS-NPs or PS-MPs in human erythrocytes and contribute to elucidating potential oxidative stress-related harmful effects, which may affect erythrocyte and systemic homeostasis. [Display omitted] • Polystyrene nano and microplastics can be internalized in human erythrocytes. • Engagement of estrogen receptors and activation of non-genomic pathways is involved. • Internalization leads to oxidative stress and alterations of cell morphology. • Oxidative stress is linked to abnormal band 3 clustering and ion transport activity. • These events can lead to erythrocyte dysfunction and impact systemic homeostasis. [ABSTRACT FROM AUTHOR]

Changes in quantitative magnetic resonance imaging (qMRI) are frequently observed during chemotherapy or radiation therapy (RT). It is hypothesized that qMRI features are reflective of underlying tissue responses. It's unknown what underlying genomic characteristics underly qMRI changes. We hypothesized that qMRI changes may correlate with DNA damage response (DDR) capacity within human tumors. Therefore, we designed the current study to correlate qMRI changes from daily RT treatment with underlying tumor transcriptomic profiles. Study participants were prospectively enrolled (National Clinical Trial 03500081). RNA expression levels for 757 genes from pretreatment biopsies were obtained using a custom panel that included signatures of radiation sensitivity and DDR. Daily qMRI data were obtained from a 1.5 Tesla MR linear accelerator. Using these images, d-slow, d-star, perfusion, and apparent diffusion coefficient-mean values in tumors were plotted per-fraction, over time, and associated with genomic pathways. A total of 1022 qMRIs were obtained from 39 patients and both genomic data and qMRI data from 27 total patients. For 20 of those patients, we also generated normal tissue transcriptomic data. Radio sensitivity index values most closely associated with tissue of origin. Multiple genomic pathways including DNA repair, peroxisome, late estrogen receptor responses, KRAS signaling, and UV response were significantly associated with qMRI feature changes (P <.001). Genomic pathway associations across metabolic, RT sensitivity, and DDR pathways indicate common tumor biology that may correlate with qMRI changes during a course of treatment. Such data provide hypothesis-generating novel mechanistic insight into the biologic meaning of qMRI changes during treatment and enable optimal selection of imaging biomarkers for biologically MR-guided RT. [ABSTRACT FROM AUTHOR]

Breast Cancer (BC) is the leading cause of cancer-related deaths in women and the most common cancer worldwide. It is classified based on its anatomical origin, the presence of Human Epidermal Growth Factor Receptor 2 (HER-2), and the presence of Estrogen Receptor (ER) and/or Progesterone Receptor (PR). Around 20% of breast cancers are HER-2 positive. While biopsy-based diagnoses are valuable in clinical settings, they have limitations in terms of sampling and interpretation. However, laboratory tests such as Immunohistochemistry (IHC) or Fluorescence In Situ Hybridization (FISH) are also limited, including being time-consuming, expensive, and requiring specialized equipment. Ongoing research and technological advancements aim to address the challenges associated with biopsybased diagnoses and laboratory tests to develop more accurate and efficient methods for assessing HER-2 status. To this end, various radioactively labeled proteins and small compounds, such as single-chain variable Fragments (scFv), F(ab')2, affibody, and nanobody, have been developed to target HER-2 using molecular array techniques. These smaller targeted compounds offer improved image quality, shorter circulating half-life, and reduced immunogenicity compared to their larger counterparts. This is due to their better biodistribution, clearance, and stability. This study investigates the current understanding and ongoing efforts in utilizing antibody fragments for molecular imaging. The specific objectives were to evaluate the advantages of antibody fragments over full-length antibodies regarding biodistribution, clearance, and stability. Additionally, this study aims to assess the current knowledge and ongoing research in utilizing antibody fragments for molecular imaging. [ABSTRACT FROM AUTHOR]

Introduction: The successful outcome of a pregnancy depends on the proper functioning uterine epithelium. DNA damage binding protein 1 and cullin 4-associated factor 2 (DCAF2), a conserved substrate receptor for the cullin 4-RING E3 ubiquitin ligase (CRL4) complex, is essential for maintaining genome stability by facilitating ubiquitin-mediated degradation of substrates. Methods: To better understand the physiological role of DCAF2 in female reproduction, we conducted a study using mice with conditional knockout (cKO) of DCAF2 in the uterus using the progesterone receptor Cre (PgrCre/+) mouse model. Results: Our results showed the cKO mice were completely infertile, despite having ovarian function. The cKO mice exhibited severely thin uteri, demonstrating notable defects in both the uterine epithelium and a lack of glands. In addition, there were impaired proliferation and differentiation of epithelial cells in the cKO mice, ultimately resulting in failed implantation. Moreover, through deciphering the uterine transcriptome of cKO mice, we revealed crucial differentially expressed genes associated with steroid signaling. Further experiments have demonstrated cKO mice exhibit elevated uterine PGR signaling and reduced estrogen receptor signaling, although the levels of progesterone and estrogen remained unaltered. These alterations may contribute to defects in epithelium. Discussion: Overall, our findings highlight a previously unrecognized but indispensable role for DCAF2 in the development of uterine luminal and glandular epithelium by orchestrating PGR and estrogen receptor responses. Its deficiency in the uterus leads to mouse infertility. [ABSTRACT FROM AUTHOR]

Breast cancer is a leading cause of female mortality and despite advancements in personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. The estrogen receptor (ER, ESR1) is expressed in two-thirds of all breast cancer, and under endocrine stress, somatic ESR1 mutations arise in approximately 30% of cases that result in endocrine resistance. We and others reported ESR1 fusions as a mechanism of ER-mediated endocrine resistance. ER fusions, which retain the activation function 1- and DNA-binding domains, harbor ESR1 exons 1 to 6 fused to an in-frame gene partner resulting in loss of the ER ligand-binding domain (LBD). We demonstrate that in a no-special type (invasive ductal carcinoma [IDC]-NST) and an invasive lobular carcinoma (ILC) cell line, ER fusions exhibit robust hyperactivation of canonical ER signaling pathways independent of estradiol or antiendocrine therapies. We employ cell line models stably overexpressing ER fusions with concurrent endogenous ER knockdown to minimize endogenous ER influence. Cell lines exhibited shared transcriptomic enrichment in pathways known to be drivers of metastatic disease, notably MYC signaling. Cells expressing the 3′ fusion partners SOX9 and YAP1 consistently demonstrated enhanced growth and cell survival. ILC cells expressing the DAB2 fusion led to enhanced growth, survival, and migration, phenotypes not appreciated in the IDC-NST DAB2 model. Herein, we report that cell line activity is subtype-, fusion-, and assay-specific, suggesting that LBD loss, the fusion partner, and the cellular landscape all influence fusion activities. Therefore, it will be critical to assess fusion frequency in the context of the clinicopathology. [ABSTRACT FROM AUTHOR]

Estrogens regulate eosinophilia in asthma and other inflammatory diseases. Further, peripheral eosinophilia and tumor-associated tissue eosinophilia (TATE) predicts a better response to immune checkpoint blockade (ICB) in breast cancer. However, how and if estrogens affect eosinophil biology in tumors and how this influences ICB efficacy has not been determined. Here, we report that estrogens decrease the number of peripheral eosinophils and TATE, and this contributes to increased tumor growth in validated murine models of breast cancer and melanoma. Moreover, estrogen signaling in healthy female mice also suppressed peripheral eosinophil prevalence by decreasing the proliferation and survival of maturing eosinophils. Inhibiting estrogen receptor (ER) signaling decreased tumor growth in an eosinophil-dependent manner. Further, the efficacy of ICBs was increased when administered in combination with anti-estrogens. These findings highlight the importance of ER signaling as a regulator of eosinophil biology and TATE and highlight the potential near-term clinical application of ER modulators to increase ICB efficacy in multiple tumor types. [ABSTRACT FROM AUTHOR]

Background: There have been some studies on the occurrence of ESR1 and 2 polymorphisms and AIS, but some data extraction is wrong, and there are no studies on the progress of AIS. Methods: Computer searches were conducted on PubMed, EMBASE, ScienceDirect and Scopus from the establishment of the database to April 2024. Cross-sectional and case-control studies on estrogen receptor ESR1, two single nucleotide polymorphisms, and the occurrence and development of AIS were collected, and statistical analysis was performed using the Revman 5.3 software. Results: In the comparison of the association between single nucleotide polymorphisms of estrogen receptors ESR1 and 2 and the occurrence and development of AIS, eight studies were included, including 2706 cases and 1736 controls.The results showed that the AA genotype [OR = 0.50,95%Cl(0.34,0.72),P = 0.0003] at the XbaI locus of ESR1,CC genotype [OR = 1.67,95%Cl(1.16,2.42), P = 0.006], C allele [OR = 1.28,95%Cl(1.03,1.59),P = 0.03], and T allele [OR = 0.78,95%] Cl(0.63,0.97),P = 0.03] at the PvuII locus of ESR1 and TT genotype [OR = 0.50,95%Cl(0.26,0.93),P = 0.03] at the AlwNI locus of ESR2 showed statistically significant differences between the progressive and stable AIS patients. Conclusion: Single nucleotide polymorphisms of ESR1 and ESR2 were not related to the occurrence of AIS; however, some of them were related to the progression of AIS. [ABSTRACT FROM AUTHOR]

Background: Malignant tumors of the breast are the most diagnosed cancers in females globally. Recent evidence suggests that carbohydrate restriction (CR), especially ketogenic diets, has become a potential treatment approach for many malignancies, including breast cancer. Tamoxifen (TAX) is a selective estrogen receptor modulator (ERM) that can reduce the risk of cancer recurrence. The current work was designed to assess the impact of CR on the proliferation of breast adenocarcinoma cells and to compare this impact with that of TAX. Study groups included: group 1: vehicle-treated mice; group 2: the Ehrlich group: injected Ehrlich ascites carcinoma (EAC) cells (2.5 × 106) in 0.25 ml isotonic saline; group 3: CR group: mice were supplied with a diet regimen of severe CR throughout the study and injected EAC at week 7; group 4: hormonal therapy (HT) group: mice in this group injected with EAC at week 7 and then received TAX at a dose of 20 mg/kg 3 times/week orally for 3 weeks; and lastly group 5: the group of combined intervention. The mice in the CR, HT, and the combined groups received Ehrlich cancer cells at the same dose and route as the Ehrlich group. Results: CR and HT groups demonstrated a significant decrease in levels of insulin-like growth factor (IGF-1), carbohydrate antigen (CA 15–3), hexokinase 2 (HK2), hypoxia-inducible factor-1 (HIF-1) α, and malondialdehyde (MDA) compared to the Ehrlich group. Additionally, the mean area % of caspase-3 was significantly increased, and the mean area % of Ki67 and estrogen receptor (ER)α was significantly decreased. Conclusions: The combined treatment demonstrated the most advantageous outcome, as evidenced by reduced CA 15–3 levels, tumor size, and the mean area % of Ki67. This suggests that the addition of severe CR to the conventional therapy of breast cancer has a beneficial effect. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is an environmentally sensitive transcription factor (TF) historically associated with carcinogenesis initiation via the activation of numerous carcinogens. Nowadays, the AhR has been attributed to multiple endogenous functions to maintain cellular homeostasis. Moreover, crosstalk, often reciprocal, has been found between the AhR and several other TFs, particularly estrogen receptors (ERs) and nuclear factor erythroid 2-related factor-2 (Nrf2). Adequate modulation of these signaling pathways seems to be an attractive strategy for cancer chemoprevention. Several naturally occurring and synthetically modified AhR or ER ligands and Nrf2 modulators have been described. Sulfur-containing derivatives of glucosinolates, such as indole-3-carbinol (I3C), and stilbene derivatives are particularly interesting in this context. I3C and its condensation product, 3,3′-diindolylmethane (DIM), are classic examples of blocking agents that increase drug-metabolizing enzyme activity through activation of the AhR. Still, they also affect multiple essential signaling pathways in preventing hormone-dependent cancer. Resveratrol is a competitive antagonist of several classic AhR ligands. Its analogs, with ortho-methoxy substituents, exert stronger antiproliferative and proapoptotic activity. In addition, they modulate AhR activity and estrogen metabolism. Their activity seems related to a number of methoxy groups introduced into the stilbene structure. This review summarizes the data on the chemopreventive potential of these classes of phytochemicals, in the context of AhR and its crosstalk modulation. [ABSTRACT FROM AUTHOR]

Simple Summary: The no specific molecular profile (NSMP) subtype of endometrial cancers remains a poorly understood class from a molecular standpoint, with a wide range of prognoses due to their internal heterogeneity. In this article, we confirm the value of a previously proposed further subdivision of NSMP into two risk classes: low-risk and high-risk; they are characterized by marked differences in oncological outcomes, including both the risk of recurrence and mortality. We are confident that this subdivision could bring significant benefits in the near future, not only in terms of modulating adjuvant therapy but also in standardizing research cohorts for more consistent and reproducible data. (1) Background: Endometrial carcinoma (EC) classified as no specific molecular profile (NSMP) represents a heterogeneous group with variable prognoses. This retrospective, single-center study aims to further stratify NSMP ECs to tailor treatment strategies and improve outcomes. (2) Methods: From 2020 to 2023, we collected data on 51 patients diagnosed with NSMP EC following the introduction of molecular profiling at our institution. Patients were retrospectively analyzed for estrogen receptor (ER) status, histotype, and grade to identify potential prognostic subgroups. (3) Results: Our analysis identified two distinct subgroups within NSMP EC: low-risk and high-risk, based on ER status, histotype, and grade. The low-risk NSMP group demonstrated significantly better survival outcomes compared to the high-risk group. With a median follow-up time of 16 moths (IQR 13.0–29.7), the disease-free survival (DFS) and overall survival (OS) for the low-risk group were 100%. For the high-risk group, the DFS and OS were 71.4% and 78.6%, respectively, which showed a statistically significantly difference (Log-Rank Mantel-Cox < 0.001). In the high-risk group, four patients experienced recurrence, and three of these patients died. (4) Conclusions: Stratifying NSMP EC into low-risk and high-risk categories based on ER status, histotype, and grade can lead to more accurate prognostic assessments. In time, it may require tailored adjuvant therapies and a personalized treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant chemotherapy is the standard of care for locally advanced breast cancer; however, it is less effective in hormone receptor (HR)-positive tumors. Therefore, we aimed to evaluate the safety and efficacy of adding an aromatase inhibitor to standard neoadjuvant chemotherapy in patients with stage II or stage III HR-positive, HER2-negative breast cancer. Adding letrozole to standard neoadjuvant chemotherapy did not significantly increase the pathologic complete response (pCR) rate; however, it enhanced the overall response rate with acceptable safety. Further research is necessary to determine the optimal neoadjuvant therapy for HR-positive, HER2-negative breast cancer to address the ongoing unmet need compared with recent advances in clinical outcomes observed in HER2-positive and triple-negative subtypes. The role of combining neoadjuvant endocrine therapy with conventional chemotherapy remains unclear; therefore, we conducted an open-label, single-center, nonrandomized phase II trial to assess the effect of this combination. Patients with previously untreated stage II or III HR-positive, HER2-negative breast cancer received concurrent letrozole 2.5 mg with standard neoadjuvant chemotherapy. The primary endpoint was pathologic complete response (pCR) at the time of surgery. We used Simon's minimax two-stage design; a pCR rate > 6% was necessary at the first stage to continue. Between November 2017 and November 2020, 53 women were enrolled in the first stage of the trial. Their median age was 49 years (range, 33–63), and 60% of them were premenopausal. Subsequently, 66% and 34% of patients with clinical stages II and III, respectively, were included; 93% had clinically node-positive disease. Two patients (4%) achieved pCR after neoadjuvant chemo–endocrine treatment, which did not satisfy the criteria for continuing to the second stage. The overall response rate was 83%. During the median follow-up of 53.7 months, the 3-year disease-free survival and overall survival rates were 87% and 98%, respectively. Neutropenia was the most common grade 3/4 adverse event (40%), but rarely led to febrile neutropenic episodes (4%). Myalgia (32%), nausea (19%), constipation (17%), heartburn (11%), oral mucositis (9%), and sensory neuropathy (9%) were frequently observed, but classified as grade 1 or 2. No deaths occurred during preoperative treatment. The addition of letrozole to standard neoadjuvant chemotherapy was safe and beneficial in terms of overall response rate, but did not provide a higher pCR rate in locally advanced HR-positive, HER2-negative breast cancer. Further research is needed to enhance neoadjuvant treatment strategies for this cancer subtype. [ABSTRACT FROM AUTHOR]

Background: Mammographic density has been associated with breast cancer risk, and is modulated by established breast cancer risk factors, such as reproductive and hormonal history, as well as lifestyle. Recent epidemiological and biological findings underscore the recognized benefits of breastfeeding in reducing breast cancer risk, especially for aggressive subtypes. Current research exploring the association among mammographic density, breastfeeding, and breast cancer is sparse. Main findings: Changes occur in the breasts during pregnancy in preparation for lactation, characterized by the proliferation of mammary gland tissues and the development of mammary alveoli. During lactation, the alveoli fill with milk, and subsequent weaning triggers the involution and remodeling of these tissues. Breastfeeding influences the breast microenvironment, potentially altering mammographic density. When breastfeeding is not initiated after birth, or is abruptly discontinued shortly after, the breast tissue undergoes forced and abrupt involution. Conversely, when breastfeeding is sustained over an extended period and concludes gradually, the breast tissue undergoes slow remodeling process known as gradual involution. Breast tissue undergoing abrupt involution displays denser stroma, altered collagen composition, heightened inflammation and proliferation, along with increased expression of estrogen receptor α (ERα) and progesterone receptor. Furthermore, elevated levels of pregnancy-associated plasma protein-A (PAPP-A) surpass those of its inhibitors during abrupt involution, enhancing insulin-like growth factor (IGF) signaling and collagen deposition. Prolactin and small molecules in breast milk may also modulate DNA methylation levels. Drawing insights from contemporary epidemiological and molecular biology studies, our review sheds light on how breastfeeding impacts mammographic density and explores its role in influencing breast cancer. Conclusion: This review highlights a clear protective link between breastfeeding and reduced breast cancer risk via changes in mammographic density. Future research should investigate the effects of breastfeeding on mammographic density and breast cancer risk among various ethnic groups and elucidate the molecular mechanisms underlying these associations. Such comprehensive research will enhance our understanding and facilitate the development of targeted breast cancer prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Cancer remains a significant global health concern. Breast cancer is a multifaceted and prevalent disease influenced by several factors, among which estrogen receptors (ERs) and the extracellular matrix (ECM) play pivotal roles. ERs, encompassing ERα and ERβ, exert significant diversity on tumor behavior, cell signaling, invasion, and metastatic potential, thus guiding breast cancer prognosis. Understanding the multifunctional connections between ERs and ECM that mediate the dynamics of tumor microenvironment is vital for unraveling the complexity of breast cancer pathobiology and identifying novel therapeutic targets. This critical review delves into the intricate nature of ERs, emphasizing their structural isoforms and the consequential impact on breast cancer outcomes. A detailed examination of ER‐mediated cell signaling pathways reveals how differential expression of ERα and ERβ isoforms influence breast cancer cell behavior. The functional ERs‐matrix interactions emerge as a pivotal factor in modulating epigenetic mechanisms of breast cancer cells, orchestrating changes in cellular phenotype and expression patterns of matrix modulators. Specifically, ERα isoforms are shown to regulate ECM signaling cascades, while the effects of ECM components on ERα activity highlight a bidirectional regulatory axis. The diversity of ERβ isoforms is also highlighted, illustrating their distinct contribution to ECM‐mediated cellular responses. This review underscores the complex interplay between ERα/β isoforms and the ECM, shedding light onto the potential therapeutic strategies targeting these interactions to improve breast cancer management. [ABSTRACT FROM AUTHOR]

ABSTRACT Melanoma is the most aggressive and deadly form of skin cancer that arises from the transformation of melanocytes, the pigment producing cells of the skin. In the year 2024 there will be approximately 10,000 new cases of melanoma diagnosed and approximately 8,000 deaths attributed to melanoma in the United States. In this study we treated a group of male and female transgenic mice that spontaneously develop metastatic melanoma, TGS, with a G‐protein‐coupled estrogen receptor agonist LNS8801 to assess the efficacy on disease progression. A second group of male and female TGS mice was also exposed to UVB irradiation to mimic exposure to sunlight. Over the course of the 32‐week experiment, visible images were taken by the small animal imaging IVIS system to track tumor progression, and blood and tissue samples were collected for molecular analyses. Results showed that sex‐biased effects were observed in the efficacy of LNS8801 and that LNS8801 shows a UV‐protective influence in both male and female TGS mice. [ABSTRACT FROM AUTHOR]

Prokineticin 1 (PROK1) is an important factor in pregnancy establishment in pigs, acting at the embryo–maternal interface and the corpus luteum (CL). Estradiol-17β (E2) is the primary pregnancy recognition signal in pigs, and its effects are augmented by luteotropic prostaglandin E2 (PGE2). On the contrary, prostaglandin F2α (PGF2α) exerts mainly a luteolytic effect. The present study aimed to elucidate whether E2, PGE2, and PGF2α regulate the expression of PROK1 and its receptors in the porcine CL and to determine the PROK1 effect on luteal endothelial cells and pathways that may be involved in this regulation. The effects of E2, PGE2, and PGF2α on the expressions of PROK1 and its receptors in the CL were studied using an in vitro model of ultrathin luteal tissue explants model. Additionally, the effects of E2 and PGE2 on the PROK1 system were determined using an in vivo approach, in which the hormones were administered into the uterine lumen to imitate their secretion by embryos. Endothelial cell proliferation was measured using the colorimetric method. E2 acting via estrogen receptors simulated the mRNA and protein expressions of PROK1 and PROKR1 in CL explants in vitro (p < 0.05). The simultaneous action of E2 with PGE2 enhanced the expression of luteal PROK1 mRNA in vitro (p < 0.05). Estradiol-17β acting alone significantly increased PROK1 mRNA levels in vivo, whereas E2 simultaneously administered with PGE2 significantly elevated the PROK1 mRNA expression and PROKR1 mRNA and protein contents in CLs adjacent to uterine horns receiving hormonal infusion compared with CLs adjacent to placebo-treated uterine horns (p < 0.01). The PROK1 protein expression was significantly higher in the CLs of pigs treated with E2, PGE2, and E2 together with PGE2 than in the control group. PGF2α increased the PROK1 mRNA content in CLs on days 12 and 14 of the estrous cycle (p < 0.05). The expression of PROKR2 at the mRNA and protein levels remained unchanged in response to in vitro and in vivo treatments. PROK1 stimulated the proliferation of luteal endothelial cells by activating the MAPK, AKT, and mTOR pathways (p < 0.05). In summary, the luteal expressions of PROK1 and PROKR1 in early pregnancy are regulated by E2 and PGE2. PROK1 stimulates luteal angiogenesis by activating the MAPK, AKT, and mTOR pathways. The regulation of luteal PROK1 expression by PGF2α indicates PROK1's putative role during luteolysis. We conclude that PROK1-PROKR1 signaling supports luteal function during CL rescue in pregnancy in pigs. [Display omitted] • Luteal expressions of prokineticin 1 and PROKR1 are regulated by primary embryonic signal (estradiol) and prostaglandin E2. • Luteolytic factor (prostaglandin F2α) is a putative regulator of luteal gene PROK1 expression during luteolysis. • Prokineticin 1 contributes to angiogenesis in the porcine CL by activation of MAPK, AKT and mTOR intracellular pathways. [ABSTRACT FROM AUTHOR]