Despite being the focal point of decades of research, female breast cancer (BC) continues to be one of the most lethal cancers in the world. Given that 80% of all diagnosed BC cases are estrogen receptor-positive (ER+) with carcinogenesis driven by estrogen-ERα signalling, current standard of care (SOC) hormone therapies are geared towards modulating the function and expression levels of estrogen and its receptors, ERα and ERβ. Currently, aromatase inhibitors (AIs), selective ER modulators (SERMs) and selective ER degraders (SERDs) are clinically prescribed for the management and treatment of ER+ BC, with the anti-aromatase activity of AIs abrogating estrogen biosynthesis, while the anti-estrogenic SERMs and SERDs antagonise and degrade the ER, respectively. The use of SOC hormone therapies is, however, significantly hampered by the onset of severe side-effects and the development of resistance. Given that numerous studies have reported on the beneficial effects of plant compounds and/or extracts and the multiple pathways through which they target ER+ breast carcinogenesis, recent research has focused on the use of dietary chemopreventive agents for BC management. When combined with SOC treatments, several of these plant components and/or extracts have demonstrated improved efficacy and/or synergistic impact. Moreover, despite a lack of in vivo investigations, plant products are generally reported to have a lower side-effect profile than SOC therapies and are therefore thought to be a safer therapeutic choice. Thus, the current review summarizes the findings from the last five years regarding the anti-aromatase and anti-estrogenic activity of plant products, as well as their synergistic anti-ER+ BC effects in combination with SOC therapies.

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.

OBJECTIVE: Cancer treatments often become ineffective because of acquired drug resistance. To characterize changes in breast cancer cells accompanying development of resistance to inhibitors of the oncogenic transcription factor, FOXM1, we investigated the suppression of cell death pathways, especially ferroptosis, in FOXM1 inhibitor-resistant cells. We also explored whether ferroptosis activators can synergize with FOXM1 inhibitors and can overcome FOXM1 inhibitor resistance.
METHODS: In estrogen receptor-positive and triple-negative breast cancer cells treated with FOXM1 inhibitor NB73 and ferroptosis activators dihydroartemisinin and JKE1674, alone and in combination, we measured suppression of cell viability, motility, and colony formation, and monitored changes in gene and protein pathway expressions and mitochondrial integrity.
RESULTS: Growth suppression of breast cancer cells by FOXM1 inhibitors is accompanied by increased cell death and alterations in mitochondrial morphology and metabolic activity. Low doses of FOXM1 inhibitor strongly synergize with ferroptosis inducers to reduce cell viability, migration, colony formation, and expression of proliferation-related genes, and increase intracellular Fe+2 and lipid peroxidation, markers of ferroptosis. Acquired resistance to FOXM1 inhibition is associated with increased expression of cancer stem-cell markers and proteins that repress ferroptosis, enabling cell survival and drug resistance. Notably, resistant cells are still sensitive to growth suppression by low doses of ferroptosis activators, effectively overcoming the acquired resistance.
CONCLUSIONS: Delineating changes in viability and cell death pathways that can overcome drug resistance should be helpful in determining approaches that might best prevent or reverse resistance to therapeutic targeting of FOXM1 and ultimately improve patient clinical outcomes.

Receptor-binding tests for the receptors of various substances are widely employed to identify drug candidates and predict the biological effects of chemical substances. Here, the results of chemicals binding to estrogen receptor (ER) reported in a validation study of the Organization for Economic Cooperation and Development TG 455 and the Hansen solubility parameter (HSP) values of the test substances were compared and examined using the Hansen sphere method, thus predicting potential HSPs that correspond to the ER-binding domain of agonists. Based on the results of the validation study and the HSP values of the test chemicals, a Hansen solubility sphere was created, and the ER potential parameter corresponding to the ER was obtained. The binding potential of the test substances to ER was predicted by comparing this potential parameter with the HSP of each test substance. These results indicate that ER binding properties can be predicted with high accuracy using the concept of HSP.

OBJECTIVE: To assess the risk stratification of clinicopathologically and molecularly classified endometrial cancer based on estrogen receptor (ER) and L1 cell adhesion molecule (L1CAM) expression.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.

It has been reported that the clinical symptoms of functional dyspepsia (FD) exacerbate upon stress while the gender-related factors have been incompletely understood. This study aims to investigate the role of sex in chronic heterotypic stress (CHS)-induced autonomic and gastric motor dysfunction. For CHS, the rats were exposed to the combination of different stressors for 7 consecutive days. Subsequently, electrocardiography was recorded in anesthetized rats to evaluate heart rate variability (HRV) for the determination of autonomic outflow and sympathovagal balance. Solid gastric emptying (GE) was measured in control and CHS-loaded male and female rats. The immunoreactivities of catecholaminergic cell marker tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), corticotropin releasing factor (CRF), and estrogen receptor (ER-α/β) were evaluated in medullary and pontine brainstem sections by immunohistochemistry. Compared with the controls, CHS significantly delayed GE in males but not in females. There was no significant sex-related difference in parasympathetic indicator HF under either control or CHS conditions. Sympathetic indicator LF was significantly higher in control females compared to the males. The higher sympathetic output in females was found to be attenuated upon CHS; in contrast, the elevated sympathetic output was detected in CHS-loaded males. No sex- or stress-related effect was observed on ChAT immunoreactivity in the dorsal motor nucleus of N.vagus (DMV). In males, greater number of TH-ir cells was observed in the caudal locus coeruleus (LC), while they were more densely detected in the rostral LC of females. Regardless of sex, CHS elevated immunoreactivity of TH throughout the LC. Under basal conditions, greater number of TH-ir cells was detected in the rostral ventrolateral medulla (RVLM) of females. In contrast, CHS remarkably increased the number of TH-ir cells in the RVLM of males which was found to be decreased in females. There was no sex-related alteration in TH immunoreactivity in the nucleus tractus solitarius (NTS) of control rats, while CHS affected both sexes in a similar manner. Compared with females, CRF immunoreactivity was prominently observed in control males, while both of which were stimulated by CHS. ER-α/β was found to be co-expressed with TH in the NTS and LC which exhibit no alteration related to either sex or stress status. These results indicate a sexual dimorphism in the catecholaminergic and the CRF system in brainstem which might be involved in the CHS-induced autonomic and visceral dysfunction occurred in males.

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by abnormal steroid hormone levels in peripheral blood and poor-quality oocytes. In the ovary, androgen is produced by theca cells, and estrogen is produced by granulosa cells. Androgen is converted to estrogen in granulosa cells, with cytochrome P450 aromatase as the limiting enzyme during this process. Estrogen receptors (ER) include ER alpha, ER beta, and membrane receptor GPR30. Studies have demonstrated that the abnormal functions of estrogen and its receptors and estradiol synthesis-related enzymes are closely related to PCOS. In recent years, some estrogen-related drugs have made significant progress in clinical application for subfertility with PCOS, such as letrozole and clomiphene. This article will elaborate on the recent advances in PCOS caused by abnormal expression of estrogen and its receptors and the application of related targeted small molecule drugs in clinical research and treatment.

UNASSIGNED: Breast cancer is the leading cause of cancer death among women worldwide. Studies about the genomic landscape of metastatic breast cancer (MBC) have predominantly originated from developed nations. There are still limited data on the molecular epidemiology of MBC in low- and middle-income countries. This study aims to evaluate the prevalence of mutations in the PI3K-AKT pathway and other actionable drivers in estrogen receptor (ER)+/HER2- MBC among Brazilian patients treated at a large institution representative of the nation\'s demographic diversity.
UNASSIGNED: We conducted a retrospective observational study using laboratory data (OC Precision Medicine). Our study included tumor samples from patients with ER+/HER2- MBC who underwent routine tumor testing from 2020 to 2023 and originated from several Brazilian centers within the Oncoclinicas network. Two distinct next-generation sequencing (NGS) assays were used: GS Focus (23 genes, covering PIK3CA, AKT1, ESR1, ERBB2, BRCA1, BRCA2, PALB2, TP53, but not PTEN) or GS 180 (180 genes, including PTEN, tumor mutation burden [TMB] and microsatellite instability [MSI]).
UNASSIGNED: Evaluation of tumor samples from 328 patients was undertaken, mostly (75.6%) with GS Focus. Of these, 69% were primary tumors, while 31% were metastatic lesions. The prevalence of mutations in the PI3K-AKT pathway was 39.3% (95% confidence interval, 33% to 43%), distributed as 37.5% in PIK3CA and 1.8% in AKT1. Stratification by age revealed a higher incidence of mutations in this pathway among patients over 50 (44.5% vs 29.1%, p=0.01). Among the PIK3CA mutations, 78% were canonical (included in the alpelisib companion diagnostic non-NGS test), while the remaining 22% were characterized as non-canonical mutations (identifiable only by NGS test). ESR1 mutations were detected in 6.1%, exhibiting a higher frequency in metastatic samples (15.1% vs 1.3%, p=0.003). Additionally, mutations in BRCA1, BRCA2, or PALB2 were identified in 3.9% of cases, while mutations in ERBB2 were found in 2.1%. No PTEN mutations were detected, nor were TMB high or MSI cases.
UNASSIGNED: We describe the genomic landscape of Brazilian patients with ER+/HER2- MBC, in which the somatic mutation profile is comparable to what is described in the literature globally. These data are important for developing precision medicine strategies in this scenario, as well as for health systems management and research initiatives.

UNASSIGNED: We executed a Mendelian randomization (MR) investigation employing two distinct cohorts of genetic instrumental variables to elucidate the causal nexus between age at menarche (AAM) and the incidence of disparate breast cancer (BC) subtypes, in addition to the incidence of BC among first-degree kin.
UNASSIGNED: We aggregated statistical data pertaining to AAM and BC from various consortia representing a homogenous population cohort. MR analysis was conducted employing inverse variance weighted (IVW) methodology as the principal approach, complemented by weighted median and MR-Egger regression techniques for an exhaustive evaluation. To evaluate the presence of pleiotropy, we applied the MR-Egger intercept test, MR-PRESSO, and leave-one-out sensitivity analysis.
UNASSIGNED: Upon exclusion of confounding SNP, an increment of one standard deviation in AAM was inversely correlated with the incidence of BC. (odds ratio [OR] 0.896, 95% confidence interval [CI] 0.831-0.968)/(OR 0.998, 95% CI 0.996-0.999) and estrogen receptor-positive (ER+) BC incidence (OR 0.895, 95% CI 0.814-0.983). It was also associated with reducing the risk of maternal BC incidence (OR 0.995, 95% CI 0.990-0.999) and sibling BC incidence (OR 0.997, 95% CI 0.994-0.999). No significant association was found between AAM and estrogen receptor-negative (ER-) BC incidence (OR 0.936, 95% CI 0.845-1.037).
UNASSIGNED: Our study substantiated the causal relationship between a delayed AAM and a diminished risk of BC in probands, as well as in their maternal progenitors and siblings. Furthermore, the analysis suggests that AAM exerts a considerable potential causal influence on the risk of developing Luminal-a/b subtype of BC.

This study systematically reviewed the role of diffusion-weighted imaging (DWI) in the assessment of molecular prognostic biomarkers in breast cancer, focusing on the correlation of apparent diffusion coefficient (ADC) with hormone receptor status and prognostic biomarkers. Our meta-analysis includes data from 52 studies examining ADC values in relation to estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki-67 status. The results indicated significant differences in ADC values among different receptor statuses, with ER-positive, PgR-positive, HER2-negative, and Ki-67-positive tumors having lower ADC values compared to their negative counterparts. This study also highlights the potential of advanced DWI techniques such as intravoxel incoherent motion and non-Gaussian DWI to provide additional insights beyond ADC. Despite these promising findings, the high heterogeneity among the studies underscores the need for standardized DWI protocols to improve their clinical utility in breast cancer management.