Breast cancer is the most common malignant tumor threatening women's health. Alteration in lipid metabolism plays an important role in the occurrence and development of many diseases, including breast cancer. The uptake, synthesis, and catabolism of lipids in breast cancer cells are significantly altered, among which the metabolism of fatty acids, cholesterols, sphingolipids, and glycolipids are most significantly changed. The growth, progression, metastasis, and drug resistance of breast cancer cells are tightly correlated with the increased uptake and biosynthesis of fatty acids and cholesterols and the up-regulation of fatty acid oxidation. Cholesterol and its metabolite 27-hydroxycholesterol promote the progression of breast cancer in a variety of ways. The alteration of lipid metabolism could promote the epithelial-mesenchymal transition of breast cancer cells and lead to changes in the tumor immune microenvironment that are conducive to the survival of cancer cells. While the accumulation of ceramide in cancer cells shows an inhibitory effect on breast cancer. This review focuses on lipid metabolism and elaborates on the research progress of the correlation between different lipid metabolism and the growth, progression, and drug resistance of breast cancer.

Does the importance of context in implementation imply that generalizing about the effects of strategies is ultimately limited? Conceptual approaches for generalizing in the presence of significant contextual heterogeneity could advance implementation research but require novel perspectives.

Drawing from perspectives from Realist approaches, Pearl's transportability framework and philosophy of science, this paper outlines a mechanism-based approach to generalizing about the effects of implementation strategies. We suggest that understanding mechanisms creates a conceptual bridge between the effects of a strategy and the influence of the implementation context. Using directed acyclic graphs to represent the mechanisms of strategies, we show how conceptualizing mediators of overall effects offer a basis for considering the effects of context. Hence, theorizing and testing a mechanistic understanding enriches the ways in which we can consider how context could change those effects. Such an approach allows us to understand how a strategy works within a given implementation context, determine what information from new contexts are needed to infer across contexts, and if that information is available, what those effects would be - thereby advancing generalizing in implementation research. We consider particular implementation strategies (e.g., Community Adherence Groups and practice facilitation) as examples to illustrate generalizing into different contexts.

Mechanisms can help implementation research by simultaneously accommodating the importance of context as well as the imperative to generalize. A shift towards a mechanism-focused approach that goes beyond identifying barriers and facilitators can enhance the value of implementation research.

In early-stage estrogen receptor-positive (ER + ) breast cancer, resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) often involve a shift away from estrogen-driven proliferation. The nature and source of compensatory growth signals driving cancer proliferation remain unknown but represent direct therapeutic targets of resistant cells. By analyzing single-cell RNA-sequencing data from serial biopsies of patient tumors, we elucidated compensatory growth signaling pathways activated in ET + CDK4/6i-resistant cancer cells, along with the intercellular growth signal communications within the tumor microenvironment. In most patient tumors, resistant cancer cells increased ERBB growth pathway activity during treatment, only partially through ERBB receptor upregulation. Concurrently, fibroblasts within the tumor increased ERBB ligand communication with cancer cells, as they differentiated to a proliferative and mesenchymal phenotype in response to TGF β signals from cancer cells. In vitro model systems demonstrated molecularly how therapy induces a mutualistic cycle of crosstalk between cancer cells and fibroblasts, fostering a growth factor-rich tumor microenvironment circumventing estrogen reliance. We show that ERBB inhibition can break this cancer-fibroblasts mutualism, targeting an acquired sensitivity of resistant cancer cells.

Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase with a diverse and integral role in cellular signalling pathways. Consequently, its dysfunction is frequently observed in disease states such as cancer, inflammation and Alzheimer's disease. A growing understanding of both PP2A and its endogenous regulatory proteins has presented numerous targets for therapeutic intervention. This provides important context for the dynamic control and dysregulation of PP2A function in disease states. Understanding the intricate regulation of PP2A signalling in disease has resulted in the development of novel pharmacological agents aimed at restoring cellular homeostasis. Herein we review the structure and function of PP2A together with pharmacological modulators, both endogenous (proteins) and exogenous (small molecules and peptides), with relevance to targeting PP2A as a future pharmacotherapeutic strategy.

This research attempted to increase the bioactivity and solubility and reduce the side effects of Tamoxifen (TMX) by using the cellulose nanocrystals (CNCs) extracted from walnut shells as a carrier and studied the interaction behavior of CNCs-TMX with hemoglobin.

The synthesized CNCs and CNCs-TMX were analyzed through the usage of XRD, FTIR, TEM, SEM, and multi-spectroscopic techniques. A real-time PCR assay was also conducted to further unravel the underlying mechanism of CNCs- TMX.

Our synthesized products including CNCs and CNCs- TMX had spherical morphologies in small sizes of 17.42 nm and 56.38 nm, respectively. The changes in FTIR spectrum signified the induced alterations in the samples functional group during the steps of preparation, while the crystallinity index of CNCs was 71.35%. Fluorescence spectroscopy confirmed the quencher functionality of CNCs-TMX along with the dominance of static quenching mechanism. Also, synchronous fluorescence displayed its binding to Hb in the vicinity of Tryptophanresidue. FRET was applied to calculate the interaction energy transfer of 0.18 nm. Next to achieving satisfactory results from oxygen-hemoglobin dissociation studies, the presence of CNCs-TMX caused a reduction in hemoglobin affinity for oxygen.

Our findings pointed out the remarkable potential of TMX-loaded CNCs, derived from walnut shell, in suppressing the proliferation, migration, and invasion of breast cancer cells by quelling the RAS/RAF/MEK/MAPK signaling pathways. The gathered data approved the promising applicability of the obtained CNCs from walnut shell in the delivery system of anti-cancer drugs throughout pharmaceutical applications.

Carbon monoxide (CO) poisoning causes significant mortality and hypoxic brain injury. Hyperbaric oxygen therapy (HBOT) may reduce delayed neurological sequelae, but poor outcomes persist. A model for predicting outcomes early after hospital admission is crucial for guiding care and early rehabilitation. In this study, we aimed to develop a clinical scoring model to predict poor outcomes in acute CO poisoning cases. The study included 176 patients aged ≥ 15 years with acute CO poisoning who were transported for HBOT between 2012 and 2023, after excluding those aged < 15 years and those in cardiac arrest on arrival. Acute CO poisoning was defined as CO exposure or COHb > 5% (> 10% for smokers). HBOT involved ≥ 1 session at 2.8 absolute atmospheres for 60 min. Predictors of poor outcomes included age, GCS < 13, burns and low C-reactive protein levels. The ABCG score (age, burns, CRP, GCS) demonstrated strong discriminative ability, with an area under the ROC curve of 0.917, sensitivity of 0.852 and specificity of 0.828. The ABCG score accurately predicts poor outcomes in acute CO poisoning and supports early intervention and treatment planning. External validation and broader application are needed for clinical adoption.

Chronic exposure to elevated levels of manganese (Mn) causes a neurological disorder referred to as manganism, with symptoms resembling Parkinson's disease (PD). The repressor element-1 silencing transcription factor (REST) has been shown to be neuroprotective in several neurological disorders, including PD, suggesting that identifying REST upregulation mechanisms is an important avenue for the development of novel therapeutics. 17β-estradiol (E2) activates the Wnt/β-catenin signaling, which is known to increase REST transcription. E2 and tamoxifen (TX), a selective estrogen receptor modulator, exerted protection against Mn toxicity. In this study, we tested if TX upregulates REST potentially via Wnt/β-catenin signaling in Cath.a-differentiated (CAD) neuronal cells using luciferase assay, qPCR, Western blot analysis, immunocytochemistry, mutagenesis, chromatin immunoprecipitation, and electrophoretic mobility shift assay. TX (1 μM) increased REST promoter activities and mRNA/protein levels and attenuated Mn (250 μM)-decreased REST transcription in parallel with TX's protective effects against Mn-induced toxicity, potentially via Wnt. TX activated Wnt/β-catenin signaling by preventing β-catenin degradation via inactivation of glycogen synthase kinase-3 beta, leading to increased β-catenin levels and its nuclear translocation and binding to T-cell factor/lymphoid enhancer binding factor sites on Wnt-responsive elements (WRE) of the REST promoter. Mutation of WRE abolished TX-induced REST promoter activity. TX-induced Wnt signaling activation was primarily via the estrogen receptor (ER)-α, although ER-β and G protein-coupled estrogen receptor 1 also mediated TX's action on REST transcription. These findings underscore the critical role of Wnt/β-catenin signaling in TX-induced REST transcription, affording protection mechanisms against Mn toxicity and neurological disorders associated with REST dysfunction.

The metabolism of drugs and foreign substances in humans typically involves multiple enzymatic steps, particularly in phase-1 biotransformation in the liver, where various cytochrome P450 monooxygenases (CYPs) play crucial roles. This complexity can lead to a wide range of metabolites. Understanding the contributions of individual CYPs and their interactions within these intricate enzyme cascades can be challenging. We recently developed an in vitro biotransformation platform employing various Chinese Hamster Ovarian (CHO) cell clones. These clones express human cytochrome P450 oxidoreductase (CPR), and each is defined by a specific human CYP enzyme expression, thus exhibiting no detectable endogenous CYP enzyme activity (mono-CYP CHO platform). In this study, we investigated whether the mono-CYP CHO platform is a suitable tool for modeling complex drug metabolization reactions in vitro. Tamoxifen (TAM) was selected as a model substance due to its role as a prodrug widely used in breast cancer therapy, where its main active metabolite, endoxifen, arises from a two-step metabolism primarily involving the CYP system. Specifically, the combined activity of CYP3A4 and CYP2D6 is believed to be essential for efficient endoxifen production. However, the physiological metabolization pathway of TAM is more complex and interconnected, and the reasons for TAM's therapeutic success and variability among patients are not yet fully understood. Analogous to our recently introduced mono-CYP3A4 CHO cells, we generated a CHO cell line expressing human CPR and CYP2D6, including analysis of CYP2D6 expression and specific activity. Comparative studies on the metabolization of TAM were performed with both mono-CYP CHO models individually and in co-culture with intact cells as well as with isolated microsomes. Supernatants were analyzed by HPLC to calculate individual CYP activity for each metabolite. All the picked mono-CYP2D6 clones expressed similar CYP2D6 protein amounts but showed different enzyme activities. Mono-CYP2D6 clone 18 was selected as the most suitable for TAM metabolization based on microsomal activity assays. TAM conversion with mono-CYP2D6 and -3A4 clones, as well as the combination of both, resulted in the formation of the expected main metabolites. Mono-CYP2D6 cells and microsomes produced the highest detected amounts of 4-hydroxytamoxifen and endoxifen, along with N-desmethyltamoxifen and small amounts of N,N-didesmethyltamoxifen. N-desmethyltamoxifen was the only TAM metabolite detected in notable quantities in mono-CYP3A4, while 4-hydroxytamoxifen and endoxifen were present only in trace amounts. In CYP2D6/3A4 co-culture and equal mixtures of both CYP microsomes, all metabolites were detected at concentrations around 50% of those in individual clones, indicating no significant synergistic effects. In conclusion, our mono-CYP CHO model confirmed the essential role of CYP2D6 in synthesizing the active TAM metabolite endoxifen and indicated that CYP2D6 is also involved in producing the by-metabolite N,N-didesmethyltamoxifen. The differences in metabolite spectra between the two mono-CYP models highlight the CYP specificity and sensitivity of our in vitro system.

Breast cancer is the second leading cause of cancer deaths among women. While tamoxifen, a commonly used drug therapy in breast cancer patients, is effective, many patients acquire tamoxifen resistance. Therefore, it is essential to identify alternative or combination therapeutics for the treatment of breast cancer. Naringenin, a naturally occurring flavonoid, has been reported to elicit antioxidant, anti-proliferative, and pro-apoptotic effects in cancer cells. The current study aimed to identify the mechanism by which naringenin induces apoptosis in tamoxifen-resistant breast cancer cells. The present study demonstrated that naringenin induced an increase in ROS, resulting in oxidative stress, impaired mitochondrial function, and apoptosis in tamoxifen-resistant breast cancer cells. Our study reports that naringenin specifically increases mitochondrial superoxide anions and hydrogen peroxide production while also causing mitochondrial dysfunction. These studies provide novel evidence for the mechanism by which naringenin induces apoptosis in tamoxifen-resistant breast cancer cells and supports the use of naringenin as a therapeutic on breast cancer cells and drug-resistant cancer cells.

Many cancer treatments can lead to reduced levels of sex hormones, which in turn may cause vasomotor symptoms (VMS) such as hot flashes. These symptoms are associated with impaired quality of life, as well as suboptimal tolerability of and adherence to cancer treatment. Hormone therapy, performed by increasing estradiol or testosterone levels, is the gold standard for treatment of VMS. However, this approach is generally contraindicated in patients with hormone-sensitive cancers. Nonhormone agents with low to moderate efficacy in controlling VMS are available, but their use may be limited by side effects and tolerability. In this narrative review, the approach to VMS in cancer patients will be discussed. The evidence for various treatment options, including novel agents such as fezolinetant that target the hypothalamic thermoregulatory pathway, will be evaluated. Finally, special considerations in different patient populations based on cancer types (eg, breast, prostate) and age groups (eg, older adults) will be explored.

We evaluated the impact of systematic bias due to loss of heterozygosity (LOH) and incomplete phenotyping in studies examining the relationship between CYP2D6 variants and breast cancer recurrence among women treated with tamoxifen.

We performed a systematic review of the literature on tamoxifen, CYP2D6 variants, and breast cancer recurrence. A quantitative bias analysis was performed to adjust for LOH and incomplete phenotyping. Bias-adjusted results were then combined in a meta-analysis.

Thirty-three studies informed the bias analysis and meta-analysis on CYP2D6 variants and breast cancer recurrence and/or mortality. An unadjusted meta-analysis suggested increased risk of recurrence and/or mortality for poor relative to normal metabolizers [RR = 1.28; 95% simulation interval (SI), 1.04-1.58] with substantial heterogeneity (I2 = 27%; P for heterogeneity = 0.07). Adjusting for LOH and incomplete genotyping resulted in a slight change in the effect estimate and a decrease in heterogeneity (RR = 1.34; 95% SI, 1.10-1.63; I2 = 0%; P for heterogeneity = 0.17). Intermediate metabolizers had a slightly increased risk of recurrence and/or mortality relative to normal metabolizers (RR = 1.15; 95% SI, 1.00-1.34; I2 = 0%; P for heterogeneity = 0.89).

Adjusting for biases such as LOH and incomplete genotyping reduced observed heterogeneity between studies. Individuals with poor CYP2D6 phenotypes were at increased risk for breast cancer outcomes compared with those with normal phenotypes.

Reduction in CYP2D6 activity was associated with an increased risk of breast cancer recurrence and/or mortality, and results underscore the importance of quantitatively adjusting for biases when aggregating study results. See related In the Spotlight, p. 221.

Tamoxifen is one of the most widely used anticancer drugs in the world. It is a safe drug with generally well-tolerated side effects and has been prescribed for the treatment of early-stage and advanced-stage or metastatic estrogen receptor α (ERα/ESR1)-positive breast cancer. Tamoxifen therapy also provides a 38% reduction of the risk of developing breast cancer in women at high risk. With the advent of newer medications targeting ERα-positive breast cancer, tamoxifen is now mainly used as adjuvant therapy for lower-risk premenopausal breast cancer and cancer prevention. It is widely accepted that tamoxifen as a selective estrogen receptor modulator exerts its therapeutic effect by competitively binding to ERα, leading to the recruitment of corepressors and inhibition of transcription of genes involved in the proliferation of breast cancer epithelium. As such, expression of ERα in breast tumors has been considered necessary for tumors to be responsive to tamoxifen therapy. However, ERα-independent effects of tamoxifen in various in vitro and in vivo contexts have been reported over the years. Importantly, the recent discovery that ERα and estrogen receptor β (ERβ/ESR2) can bind tumor suppressor protein p53 with functional consequences has provided new insights into the mechanisms underlying response to tamoxifen therapy and resistance. Furthermore, these findings have paved the way for broadening the use of tamoxifen by potentially repurposing it to treat triple negative (negative for ERα, human epidermal growth factor receptor 2, and progesterone receptor) breast cancer. Herein, we summarize these developments and discuss their mechanistic underpinnings and clinical implications.

Estrogens have been associated with an increase in breast cancer risk. Yet emerging clinical and experimental evidence points to progestogens [endogenous progesterone or synthetic progesterone (progestin)] as the primary hormonal driver underlying seemingly estrogen-associated breast cancer risk. Estrogens may contribute to breast cancer risk indirectly by induction of the progesterone receptor and thus amplifying progesterone signaling. Large studies of hormonal contraceptives suggest that the small increase in breast cancer risk from hormonal contraceptives is mainly attributable to progestins, not estrogens. Estrogen-plus-progestin hormone replacement therapy (HRT) has consistently shown an increase in breast cancer risk among postmenopausal women, whereas estrogen-alone HRT has little impact on breast cancer risk in naturally or surgically menopausal women. In particular, the long-term follow-up of the Women's Health Initiative (WHI) randomized trials suggests a benefit of estrogen alone. Recent data further indicate that endogenously elevated estrogen during assisted reproductive technology (ART) exhibits little adverse effect on or potentially a reduction in breast cancer risk and recurrence. Also, accumulating evidence suggests that inhibition of progesterone signaling is a critical mechanism underlying the risk-reducing and therapeutic effects of antiestrogens. Estrogen HRT has shown an array of proven benefits, including ameliorating menopausal symptoms and improving bone health. Collective evidence thus suggests that estrogen HRT is likely to offer health benefits to perimenopausal or postmenopausal women, including breast cancer survivors, as well as young BRCA1/2 carriers with prophylactic oophorectomy for ovarian cancer prevention.

Circular RNAs (circRNAs) have garnered substantial attention due to their distinctive circular structure and gene regulatory functions, establishing them as a significant class of functional non-coding RNAs in eukaryotes. Studies have demonstrated that circRNAs can interact with RNA-binding proteins (RBPs), which play crucial roles in tumorigenesis, metastasis, and drug response in cancer by influencing gene expression and altering the processes of tumor initiation and progression. This review aims to summarize the recent advances in research on circRNA-protein interactions (CPIs) and discuss the functions and mode of action of CPIs at various stages of gene expression, including transcription, splicing, translation, and post-translational modifications in the context of cancer. Additionally, we explore the role of CPIs in tumor drug resistance to gain a deeper understanding of their potential applications in the development of new anti-cancer therapeutic approaches.

Breast cancer is one of the main causes of mortality in women globally. Early and accurate diagnosis represents a milestone in cancer management. Several breast cancer diagnostic agents are available. Many chemotherapeutic agents in conventional dosage forms are approved; nevertheless, they lack cancer cell specificity, resulting in improper treatment and undesirable side effects. Recently, nanotheranostics has emerged as a new paradigm to achieve safe and effective cancer diagnosis and management.

This review provides insight into breast cancer epidemiology, barriers hindering the early diagnosis, and effective delivery of chemotherapeutics. Also, conventional diagnostic agents and recent nanotheranostic platforms have been used in breast cancer. In addition, mechanisms of cancer cell targeting and nano-carrier surface functionalization as an effective approach for chemotherapeutic targeting were reviewed along with future perspectives.

We proposed that modified nano-carriers may provide an efficacious approach for breast cancer drug targeting. These nanotheranostics need more clinical evaluations to confirm their efficacy in cancer management. In addition, we recommend the use of artificial intelligence (AI) as a promising approach for early and efficient assessment of breast lesions. AI allows better interpretation and analysis of nanotheranostic data, which minimizes misdiagnosis and avoids the belated intervention of health care providers.

Both chemotherapy (CT) and endocrine therapy (ET) play important roles in the systemic treatment of breast cancer (BC). However, previous studies have shown an antagonistic effect when CT and ET are administered simultaneously. Therefore, sequential administration is more effective than combined administration. The current guidelines and consensus recommend a sequential schedule of CT and ET for patients with hormone receptor-positive (HR+) BC. However, with the continuous introduction of new endocrine drugs, the question of whether the simultaneous administration of CT and ET is superior to sequential therapy has surfaced again as a hot topic of clinical concern. Recent studies have shown that the combination of certain chemotherapeutic agents with endocrine drugs has a synergistic effect. This review aims to summarize the new advances achieved in recent years on the old topic of CT combined with ET in the treatment of BC.

Premenopausal women with early stage, high risk hormone receptor positive breast cancer are at risk of early discontinuation of adjuvant endocrine therapy (ET), primarily because of toxicity, which can increase the risk of disease recurrence and death. We hypothesize that identification of bothersome symptoms between clinic visits, and automated notification of clinicians about symptoms, will result in improved persistence with ET.

Pre- and perimenopausal women planning to receive adjuvant treatment with tamoxifen or an aromatase inhibitor plus ovarian function suppression or ablation for treatment of breast cancer are eligible. A total of 540 participants will be enrolled and randomized 1:1 to patient education with or without Active Symptom Monitoring (ASM). The ASM intervention includes 6 symptom questions (hot flashes, sadness, anxiety, insomnia, vaginal dryness, joint pain) that will be completed via text, email, or telephone weekly for 24 weeks, then every 4 weeks for 48 weeks. All participants will complete a battery of questionnaires every 12 weeks to examine symptoms, beliefs about medicine, self-efficacy, and ET adherence. Optional blood draws will be collected at baseline and after 12, 48, and 72 weeks of therapy to examine estradiol and ET concentrations. The primary endpoint is time to nonpersistence with initially prescribed ET within the first 72 weeks, evaluated using Kaplan-Meier plots and multivariable Cox regression.

We expect early identification and management of ET-related toxicities to improve persistence with breast cancer therapy, breast cancer outcomes, and quality of life for premenopausal women at high risk of breast cancer recurrence.

govNCT05568472.

One of the most famous and heterogeneous cancers worldwide is breast cancer (BC). Owing to differences in the gene expression profiles and clinical features of distinct BC subtypes, different treatments are prescribed for patients. However, even with more thorough pathological evaluations of tumors than in the past, available treatments do not perform equally well for all individuals. Precision medicine is a new approach that considers the effects of patients' genes, lifestyle, and environment to choose the right treatment for an individual patient. As a powerful tool, the organoid culture system can maintain the morphological and genetic characteristics of patients' tumors. Evidence also shows that organoids have high predictive value for patient treatment. In this review, a variety of BC studies performed on organoid culture systems are evaluated. Additionally, the potential of using organoid models in BC translational research, especially in immunotherapy, drug screening, and precision medicine, has been reported.

Inter- and intra-tumor heterogeneity is considered a significant factor contributing to the development of endocrine resistance in breast cancer. Recent advances in single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) allow us to explore inter- and intra-tumor heterogeneity at single-cell resolution. However, such integrated single-cell analysis has not yet been demonstrated to characterize the transcriptome and chromatin accessibility in breast cancer endocrine resistance.

In this study, we conducted an integrated analysis combining scRNA-seq and scATAC-seq on more than 80,000 breast tissue cells from two normal tissues (NTs), three primary tumors (PTs), and three tamoxifen-treated recurrent tumors (RTs). A variety of cell types among breast tumor tissues were identified, PT- and RT-specific cancer cell states (CSs) were defined, and a heterogeneity-guided core signature (HCS) was derived through such integrated analysis. Functional experiments were performed to validate the oncogenic role of BMP7, a key gene within the core signature.

We observed a striking level of cell-to-cell heterogeneity among six tumor tissues and delineated the primary to recurrent tumor progression, underscoring the significance of these single-cell level tumor cell clusters classified from scRNA-seq data. We defined nine CSs, including five PT-specific, three RT-specific, and one PT-RT-shared CSs, and identified distinct open chromatin regions of CSs, as well as a HCS of 137 genes. In addition, we predicted specific transcription factors (TFs) associated with the core signature and novel biological/metabolism pathways that mediate the communications between CSs and the tumor microenvironment (TME). We finally demonstrated that BMP7 plays an oncogenic role in tamoxifen-resistant breast cancer cells through modulating MAPK signaling pathways.

Our integrated single-cell analysis provides a comprehensive understanding of the tumor heterogeneity in tamoxifen resistance. We envision this integrated single-cell epigenomic and transcriptomic measure will become a powerful approach to unravel how epigenetic factors and the tumor microenvironment govern the development of tumor heterogeneity and to uncover potential therapeutic targets that circumvent heterogeneity-related failures.

Breast cancer is the most common cancer in women and the 2nd most common cancer worldwide, yearly impacting over 2 million females and causing 650 thousand deaths. It has been widely studied, but its epigenetic variation is not entirely unveiled. We aimed to identify epigenetic mechanisms impacting the expression of breast cancer related genes to detect new potential biomarkers and therapeutic targets. We considered The Cancer Genome Atlas database with over 800 samples and several omics datasets such as mRNA, miRNA, DNA methylation, which we used to select 2701 features that were statistically significant to differ between cancer and control samples using the Monte Carlo Feature Selection and Interdependency Discovery algorithm, from an initial total of 417,486. Their biological impact on cancerogenesis was confirmed using: statistical analysis, natural language processing, linear and machine learning models as well as: transcription factors identification, drugs and 3D chromatin structure analyses. Classification of cancer vs control samples on the selected features returned high classification weighted Accuracy from 0.91 to 0.98 depending on feature-type: mRNA, miRNA, DNA methylation, and classification algorithm. In general, cancer samples showed lower expression of differentially expressed genes and increased β-values of differentially methylated sites. We identified mRNAs whose expression is well explained by miRNA expression and differentially methylated sites β-values. We recognized differentially methylated sites possibly affecting NRF1 and MXI1 transcription factors binding, causing a disturbance in NKAPL and PITX1 expression, respectively. Our 3D models showed more loosely packed chromatin in cancer. This study successfully points out numerous possible regulatory dependencies.

Immunotherapy stands as the frontrunner in treatment strategies imparting efficient remission in various types of cancer. In fact, emerging breakthroughs with immune checkpoint inhibitors (ICI) in a spectrum of cancers have evoked interest in research related to the potential effects of immunotherapy in breast cancer patients. A major challenge with breast cancer is the molecular heterogeneity that limits the efficacy of many therapeutic regimes. Clinical trials have shown favorable clinical outcomes with immunotherapeutic options in some subtypes of breast cancer. However, ICI monotherapy may not be sufficient for all breast cancer patients, emphasizing the need for combinatorial approaches. Ongoing research is focused on untangling the interplay of ICI with established as well as novel anticancer therapeutic regimens in preclinical models of breast cancer. Our review will analyze the existing research regarding the mechanisms and clinical impact of immunotherapy for the treatment of breast cancer. We shall evaluate the role of immune cell modulation for improved therapeutic response in breast cancer patients. This review will provide collated evidences about the current clinical trials that are testing out the implications of immunotherapy in conjunction with traditional treatment modalities in breast cancer and summarize the potential future research directions in the field. In addition, we shall underline the recent findings related to microbiota modulation as a key regulator of immune therapy response in cancer patients and its plausible applications in breast cancer.

Given the high prevalence of breast cancer and the diverse genetic backgrounds of patients, a growing body of research emphasizes the importance of pharmacogenetic-based pharmacokinetic analysis in optimizing treatment outcomes. The treatment of breast cancer involves multiple drugs whose metabolism and efficacy are influenced by individual genetic variations. Genetic polymorphisms in drug-metabolizing enzymes and transport proteins are crucial in the regulation of pharmacokinetics. Our review aims to investigate the opportunities and challenges of pharmacogenomic-based pharmacokinetic analysis as a precision medicine tool in breast cancer management.

Breast cancer stands as the most frequently diagnosed life-threatening cancer among women worldwide. Understanding patients' drug experiences is essential to improving treatment strategies and outcomes. In this research, we conduct knowledge discovery on breast cancer drugs using patients' reviews. A new machine learning approach is developed by employing clustering, text mining and regression techniques. We first use Latent Dirichlet Allocation (LDA) technique to discover the main aspects of patients' experiences from the patients' reviews on breast cancer drugs. We also use Expectation-Maximization (EM) algorithm to segment the data based on patients' overall satisfaction. We then use the Forward Entry Regression technique to find the relationship between aspects of patients' experiences and drug's effectiveness in each segment. The textual reviews analysis on breast cancer drugs found 8 main side effects: Musculoskeletal Effects, Menopausal Effects, Dermatological Effects, Metabolic Effects, Gastrointestinal Effects, Neurological and Cognitive Effects, Respiratory Effects and Cardiovascular. The results are provided and discussed. The findings of this study are expected to offer valuable insights and practical guidance for prospective patients, aiding them in making informed decisions regarding breast cancer drug consumption.

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.

This study aimed to evaluate characteristics of endometrial surveillance in women treated for breast cancer to build a clinical prediction model.

A multicentric retrospective cohort study was conducted at two tertiary-care university hospitals from January 2020 to June 2023. Perimenopausal and postmenopausal women treated for breast cancer were categorized into two groups: patients with and without diagnosis of endometrial malignancy (endometrial carcinoma) or premalignancy (atypical endometrial hyperplasia). Characteristics of breast cancer and ultrasonographic and hysteroscopic examinations were compared. A prediction model for endometrial malignancy was built using logistic regression. Predictive accuracy was assessed using the receiver operating characteristic (ROC) curve and goodness of fit using the Hosmer-Lemeshow test.

One hundred and thirty-two (28 with premalignancy or malignancy and 104 without malignancy) women were analyzed. A nomogram was produced for prediction model development utilizing the presence and duration in months of abnormal uterine (BL)eeding, ultrasound (US) vascular pattern and echogenicity and (H)ysteroscopic appearance of endometrium (BLUSH) as determined by logistic regression. Sensitivity and specificity were 79.17% and 95.19%, respectively, with an area under ROC curve of 0.965, indicating good accuracy. Good goodness of fit and prediction stability were indicated by the calibration curve and Hosmer-Lemeshow test (χ2 = 26.36; p = 0.999).

Breast cancer survivors undergoing endometrial surveillance might benefit from a potentially useful prediction model based on hysteroscopic appearance, ultrasonographic uniformity of endometrium, Doppler flow and presence of abnormal uterine bleeding.

Chemotherapy remains a commonly used and important treatment option for metastatic breast cancer. A majority of ER+ metastatic breast cancer patients ultimately develop resistance to chemotherapy, resulting in disease progression. We hypothesized that an "evolutionary double-bind", where treatment with one drug improves the response to a different agent, would improve the effectiveness and durability of responses to chemotherapy. This approach exploits vulnerabilities in acquired resistance mechanisms. Evolutionary models can be used in refractory cancer to identify alternative treatment strategies that capitalize on acquired vulnerabilities and resistance traits for improved outcomes. To develop and test these models, ER+ breast cancer cell lineages sensitive and resistant to chemotherapy are grown in spheroids with varied initial population frequencies to measure cross-sensitivity and efficacy of chemotherapy and add-on treatments such as disulfiram combination treatment. Different treatment schedules then assessed the best strategy for reducing the selection of resistant populations. We developed and parameterized a game-theoretic mathematical model from this in vitro experimental data, and used it to predict the existence of a double-bind where selection for resistance to chemotherapy induces sensitivity to disulfiram. The model predicts a dose-dependent re-sensitization (a double-bind) to chemotherapy for monotherapy disulfiram.

The effects of hormonal therapy, estrogen-based hormone replacement therapy (HRT), and anti-tumor hormone therapy, such as tamoxifen, on the physiological uptake of the endometrium on 2-deoxy-2[18F]fluoro-D-glucose ([18F]F-FDG) positron emission tomography (PET) in postmenopausal women have not been determined. We explored the effect of hormone therapy, particularly HRT, on physiological uptake in the endometrium of postmenopausal women.

Postmenopausal women receiving hormone therapy who underwent cancer screening using PET/computed tomography (CT) between June 2016 and April 2023 were included in the hormone therapy group (n = 21). Postmenopausal women with no history of hormone therapy were included in the control group (n = 49). First, the physiological endometrial uptake at menopausal age and at least 1 year thereafter was compared quantitatively (SUVmax) and qualitatively (4-point scale) in the control group, to assess when the endometrium ceased to show significant physiological [18F]F-FDG uptake after menopause. Endometrial uptake was compared between the hormone therapy and control groups. The association between HRT duration (months) and endometrial uptake (SUVmax) was evaluated. Endometrial thickness, measured using transvaginal ultrasonography, was also compared between the two groups.

Endometrial uptake was significantly reduced both qualitatively and quantitatively (P < 0.05) at least 1 year after menopause in control patients, by which time most women (89.8%) no longer had significant endometrial uptake. The hormone therapy group (n = 21) showed higher FDG uptake in the endometrium compared to the control group (median SUVmax: 2.3 vs 1.9, P = 0.0011), as well as a higher visual score (P < 0.0001). HRT duration did not correlate with endometrial uptake (P = 0.097). Endometrial thickness in the hormone therapy group was significantly thicker than in the control group (median: 3.9 mm vs 1.8 mm, P = 0.002).

Hormone therapy may affect physiological uptake in the endometrium in postmenopausal women.

Breast cancer is the most frequently diagnosed cancer in women worldwide, and non-adherence to adjuvant hormonotherapy can negatively impact cancer recurrence and relapse. Non-adherence is associated with side effects of hormonotherapy. Pharmacological strategies to mitigate the side effects include coadministration of antidepressants, however patients remain non-adherent. The aim of this work was to develop medicines containing both hormonotherapy, tamoxifen (20 mg), along with anti-depressants, either venlafaxine (37.5 or 75 mg) or duloxetine (30 or 60 mg), to assess the acceptability and efficacy of this personalised approach for mitigating tamoxifen side effects in a clinical trial. A major criterion for the developed medicines was the production rate, specified at minimum 200 dosage units per hour to produce more than 40,000 units required for the clinical trial. A novel capsule filling approach enabled by the pharmaceutical 3D printer M3DIMAKER 2 was developed for this purpose. Firstly, semi-solid extrusion 3D printing enabled the filling of tamoxifen pharma-ink prepared according to French compounding regulation, followed by filling of commercial venlafaxine or duloxetine pellets enabled by the development of an innovative pellet dispensing printhead. The medicines were successfully developed and produced in the clinical pharmacy department of the cancer hospital Gustave Roussy, located in Paris, France. The developed medicines satisfied quality and production rate requirements and were stable for storage up to one year to cover the duration of the trial. This work demonstrates the feasibility of developing and producing combined tamoxifen medicines in a hospital setting through a pharmaceutical 3D printer to enable a clinical trial with a high medicines production rate requirement.

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between 'borrowed' and 'intrinsic' components. Bioinformatics prioritized one of the 'borrowed' components, CCDC88A /GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced ∼20% of both the 'borrowed' and the 'intrinsic' gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.

Estrogen receptors (ERs) are located in both healthy and neoplastic tissues. The type of estrogen receptor expressed varies depending on its location, tumor type, and species. Estrogen action is mediated by binding to ER and activating the transcriptional and signaling processes that result in the control of gene expression. There are two main types of estrogen receptors: ER alpha (ERα) and ER beta (ERβ). Both receptors are functionally different, they may act antagonistically and are distributed in different tissues but their structure is similar - as they are composed of 5 different domains: A/B, C, D, E, and F. The signaling pathway and hence regulation of the gene expression by ERs is a complex and multifactorial process that involves both genomic and nongenomic actions. In the human reproductive tract, both ERα and β are present, with predominant expression of ERβ, while there are no satisfactory data distinguishing the type of ERs expressed in the canine reproductive tract. In mammary gland neoplasia, a decreased or lacking ERα expression in humans is associated with a poorer prognosis. This is similar to dogs, where higher ERα expression intensity was noted in benign tumors than in carcinomas. In human hematopoietic malignancies, ERβ is a predominant receptor. Selective and non-selective ERβ agonists have an antiproliferative and pro-apoptotic effect on human lymphoma cell lines and may be effective in the therapy of ERβ positive lymphomas and leukemias. In canine lymphoma tissues, none or only marginal expression of ERs was detected over the decades. Considering available data, we conducted preliminary studies proving that, in contrast to humans, the dominant ER expressed in canine hematopoietic tumors is ERα.

Breast cancer is the most prevalent cancer among women and the leading cause of cancer-related deaths in this population. Recent advances in Immunotherapy, or combined immunotherapy, offering a more targeted and less toxic approach, expand the survival rate of patients more than conventional treatment. Notably, hydrogels, a versatile platform provided promising avenues to combat breast cancer in preclinical studies and extended to clinical practices. With advantages such as the alternation of tumor microenvironment, immunomodulation, targeted delivery of therapeutic agents, and their sustained release at specific sites of interest, hydrogels can potentially be used for the treatment of breast cancer. This review highlights the advantages, mechanisms of action, stimuli-responsiveness properties, and recent advancements of hydrogels for treating breast cancer immunotherapy. Moreover, post-treatment and its clinical translations are discussed in this review. The integration of hydrogels in immunotherapy strategies may pave the way for more effective, personalized, and patient-friendly approaches to combat breast cancer, ultimately contributing to a brighter future for breast cancer patients.

Hot flashes (HF) are a common adverse event of prolonged tamoxifen use in women with estrogen receptor-positive breast cancer, impacting psychiatric health and quality of life. While desvenlafaxine does not interact with tamoxifen, its efficacy and safety in breast cancer patients remain unstudied. This phase 3, four-week, multi-center, three-arm, parallel-group, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of desvenlafaxine for treating HF in women with breast cancer taking tamoxifen, assessing potential differential effects in patients with psychiatric and inflammatory conditions. Between December 2017 and February 2019, 57 women aged 19 or older, regularly taking tamoxifen as adjuvant therapy, experiencing moderate-to-severe HFs for more than a month, were randomized to receive desvenlafaxine 50 mg/day (D-50), desvenlafaxine 100 mg/day (D-100), or placebo for four weeks. The primary endpoint was the change rate in HF scores over four weeks, with adverse events as a secondary endpoint. Both desvenlafaxine arms demonstrated greater HF score reductions compared to placebo: D-50 (2.20 points/week, 95% CI: 0.71, 3.68) and D-100 (2.34 points/week, 95% CI: 0.92, 3.76). Notably, D-50 arm showed significantly greater efficacy in patients with depression or elevated inflammation. Desvenlafaxine offers an effective and safe treatment regimen for HF in women with breast cancer taking tamoxifen. The presence of depression and inflammation may guide optimal desvenlafaxine dosing. (Trial Registration: ClinicalTrials.gov Identifier: NCT02819921).

It is well known that adjuvant tamoxifen treatment for breast cancer in postmenopausal women decreased bone loss. However, the effects of adjuvant tamoxifen therapy on bone mineral density (BMD) in premenopausal patients with breast cancer remains uncertain. Tamoxifen would have a potential impact of premenopausal BMD on health. The aim of this meta-analysis was to assess this in premenopausal women with primary breast cancer.

Through April 2020, studies reporting BMD changes of lumbar spine or hip in premenopausal women with primary breast cancer treated with adjuvant tamoxifen and tamoxifen plus chemotherapy or ovarian function suppression (OFS) were collected from EMBASE and PubMed. The meta-analysis was performed using random effects model of the standardized mean difference (SMD) of BMD in patients.

A total of 1432 premenopausal patients were enrolled in eight studies, involving 198 patients treated with tamoxifen alone in three studies. After a 3-year median follow-up, adjuvant tamoxifen decreased the lumbar spinal and hip BMD by as much as an SMD of -1.17 [95% confidence interval (CI); -1.58 to -0.76)] and -0.66 (95% CI, -1.55 to 0.23), respectively. In subgroup analysis in patients treated adjuvant tamoxifen and tamoxifen plus chemotherapy or OFS according to follow-up duration, the bone change of < 3 years follow-up group was -0.03 SMD (95% CI, -0.47 to 0.41) and that of ≥ 3 years follow-up group was -1.06 SMD (95% CI, -1.48 to -0.64). Compared with patients who received tamoxifen alone, patients who received combination therapy with chemotherapy or OFS showed lesser bone loss at the lumbar spine.

Our meta-analysis demonstrated that adjuvant tamoxifen therapy in premenopausal patients caused bone loss after 3 years of follow-up, especially at the lumbar spines. For a definite evaluation of the adverse effects of tamoxifen on bone, it is necessary to accumulate more relevant studies.

Raloxifene, a selective oestrogen receptor modulator (SERM), has demonstrated efficacy in the prevention and therapy of oestrogen receptor-positive (ER+) breast cancer, with some degree of effectiveness against triple-negative forms. This suggests the presence of oestrogen receptor-independent pathways in raloxifene-mediated anticancer activity. To enhance the potential of raloxifene against the most aggressive breast cancer cells, hybrid molecules combining the drug with a metal chelator moiety have been developed. In this study, we synthetically modified the structure of raloxifene by incorporating a 2,2'-bipyridine (2,2'-bipy) moiety, resulting in [6-methoxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]-[4-(2,2'-bipyridin-4'-yl-methoxy)phenyl]methanone (bipyraloxifene). We investigated the cytotoxic activity of both raloxifene and bipyraloxifene against ER+ breast adenocarcinomas, glioblastomas, and a triple-negative breast cancer (TNBC) cell line, elucidating their mode of action against TNBC. Bipyraloxifene maintained a mechanism based on caspase-mediated apoptosis but exhibited significantly higher activity and selectivity compared to the original drug, particularly evident in triple-negative stem-like MDA-MB-231 cells.

Tamoxifen is a non-steroidal selective oestrogen receptor modulator commonly used in the treatment of breast cancer. It is associated with the development of fatty liver and steatohepatitis however drug-induced liver injury is rare. We report a woman in her 50s who developed malaise with an acute moderate aminotransferase elevation without jaundice 6 months after starting tamoxifen. She was not commenced on any other recent drugs and extensive investigation including infective and autoimmune liver screen, cross-sectional imaging and FibroScan were unremarkable. Liver biopsy revealed moderate lobular hepatitis with hepatocyte drop-out. Tamoxifen was ceased and the liver enzymes showed resolution over the following 3 months and improvement of her symptoms.

Estrogen receptor (ER) β (ERβ) is the second ER subtype that mediates the effects of estrogen in target tissues along with ERα that represents a validated biomarker and target for endocrine therapy in breast cancer. ERα was the only known ER subtype until 1996 when the discovery of ERβ opened a new chapter in endocrinology and prompted a thorough reevaluation of the estrogen signaling paradigm. Unlike the oncogenic ERα, ERβ has been proposed to function as a tumor suppressor in breast cancer, and extensive research is underway to uncover the full spectrum of ERβ activities and elucidate its mechanism of action. Recent studies have relied on new transgenic models to capture effects in normal and malignant breast that were not previously detected. They have also benefited from the development of highly specific synthetic ligands that are used to demonstrate distinct mechanisms of gene regulation in cancer. As a result, significant new information about the biology and clinical importance of ERβ is now available, which is the focus of discussion in the present article.

During breast cancer treatment, approximately half of the patients are prescribed psychotropic medication, such as selective serotonin reuptake inhibitors (SSRIs). Escitalopram oxalate is an SSRI used as an antidepressant.

In this study, by creating a breast cancer microenvironment with THP-1, MCF-7 and MDA-MB-231 breast cancer co-culture models were created.

MCF-7, MDA-MB-231, and THP-1 cell lines to determine the concentration range of the cytotoxic effect of escitalopram oxalate MTS and MTT test were used. IC50 values were determined by the xCELLigence real-time cell analysis (RTCA) system. Apoptotic activities and cytokine levels were determined by flow cytometry.

In the xCELLigence real-time analysis made according to the results, the IC50 value of escitalopram oxalate was measured as 13.7 μM for MCF-7 and 10.9 μM for MDA-MB-231. The IC50 value was measured as 54.6 μM for MCF-7 and 58.4 μM for MDA-MB-231 in xCELLigence analysis with tamoxifen. According to the MTS test results, the IC50 value of tamoxifen for THP-1 was 92.03 μM and the IC50 value for escitalopram oxalate was 95.32 μM. In the co-culture model, the immunological effects of escitalopram oxalate on MCF-7 cells were 2.8%, 11.1%, 15.6%, 10.6%, and 12.1% for interleukin (IL)-1β, IL-6, IL-8, IL-10, and TNF-α, respectively, while MDA effects on MB-231 cells, respectively, were 2.1%, 15.9%, 16.2%, 8.8%, and 11.8%.

According to the results obtained, it was concluded that the immunological effects of escitalopram oxalate are more effective than tamoxifen and that it can be used as an adjunctive agent in breast cancer treatment.

Breast cancer (BC) is a global health concern and the leading cause of cancerous death among women across the world, BC has been characterized by fresh lump in the breast or underarm (armpit), thickened or swollen. Worldwide estimated 9.6 million deaths in 2018-2019. Numerous drugs have been approved by FDA for BC treatment but showed numerous adverse effects like bioavailability issues, selectivity issues, and toxicity issues. Therefore, there is an immediate need to develop new molecules that are non-toxic and more efficient for treating cancer. Isoxazole derivatives have gained popularity over the few years due to their effective antitumor potential. These derivatives work against cancer by inhibiting the thymidylate enzyme, inducing apoptosis, inhibiting tubulin polymerization, protein kinase inhibition, and aromatase inhibition. In this study, we have concentrated on the isoxazole derivative with structure-activity relationship study, various synthesis techniques, mechanism of action, docking, and simulation studies pertaining to BC receptors. Hence the development of isoxazole derivatives with improved therapeutic efficacy will inspire further progress in improving human health.Communicated by Ramaswamy H. Sarma.

Ubiquitin (Ub) protein ligase E3 component n-recognin 5 (UBR5), as a crucial Ub ligase, plays a pivotal role in the field of cell biology, attracting significant attention for its functions in regulating protein degradation and signaling pathways. This review delves into the fundamental characteristics and structure of UBR5. UBR5, through ubiquitination, regulates various key proteins, directly or indirectly participating in cell cycle control, thereby exerting a direct impact on the proliferation of tumor cells. Meanwhile, we comprehensively review the expression levels of UBR5 in different types of tumors and its relationship with tumor development, providing key clues for the role of UBR5 in cancer. Furthermore, we summarize the current research status of UBR5 in cancer treatment. Through literature review, we find that UBR5 may play a crucial role in the sensitivity of tumor cells to radiotherapy chemotherapy, and other anti-tumor treatment, providing new insights for optimizing cancer treatment strategies. Finally, we discuss the challenges faced by UBR5 in cancer treatment, and looks forward to the future research directions. With the continuous breakthroughs in technology and in-depth research, we hope to further study the biological functions of UBR5 and lay the foundation for its anti-tumor treatment.

Annual breast cancer (BCa) deaths have declined since its apex in 1989 concomitant with widespread adoption of hormone therapies that target estrogen receptor alpha (ERα), the prominent nuclear receptor expressed in ∼80% of BCa. However, up to ∼50% of patients who are ER+ with high-risk disease experience post endocrine therapy relapse and metastasis to distant organs. The vast majority of BCa mortality occurs in this setting, highlighting the inadequacy of current therapies. Genomic abnormalities to ESR1, the gene encoding ERα, emerge under prolonged selective pressure to enable endocrine therapy resistance. These genetic lesions include focal gene amplifications, hotspot missense mutations in the ligand binding domain, truncations, fusions, and complex interactions with other nuclear receptors. Tumor cells utilize aberrant ERα activity to proliferate, spread, and evade therapy in BCa as well as other cancers. Cutting edge studies on ERα structural and transcriptional relationships are being harnessed to produce new therapies that have shown benefits in patients with ESR1 hotspot mutations. In this review we discuss the history of ERα, current research unlocking unknown aspects of ERα signaling including the structural basis for receptor antagonism, and future directions of ESR1 investigation. In addition, we discuss the development of endocrine therapies from their inception to present day and survey new avenues of drug development to improve pharmaceutical profiles, targeting, and efficacy.

This review comprehensively explores the gene BCAR3, detailing its regulation at the gene, mRNA, and protein structure levels, and delineating its multifunctional roles in cellular signaling within cancer contexts. The discussion covers BCAR3's involvement in integrin signaling and its impact on cancer cell migration, its capability to induce anti-estrogen resistance, and its significant functions in cell cycle regulation. Further highlighted is BCAR3's modulation of immune responses within the tumor microenvironment, a novel area of interest that holds potential for innovative cancer therapies. Looking forward, this review outlines essential future research directions focusing on transcription factor binding studies, isoform-specific expression profiling, therapeutic targeting of BCAR3, and its role in immune cell function. Each segment builds towards a holistic understanding of BCAR3's operational mechanisms, presenting a critical evaluation of its therapeutic potential in oncology. This synthesis aims to not only extend current knowledge but also catalyze further research that could pivotally influence the development of targeted cancer treatments.

In tumors, somatic mutagenesis presumably drives the DNA damage response (DDR) via altered regulatory pathways, increasing genomic instability and proliferative activity. These considerations led to the standard therapeutic strategy against cancer: the disruption of mutation-activated DNA repair pathways of tumors.

Justifying that cancer cells are not enemies to be killed, but rather that they are ill human cells which have the remnants of physiologic regulatory pathways.

1. Genomic instability and cancer development may be originated from a flaw in estrogen signaling rather than excessive estrogen signaling; 2. Healthy cells with genomic instability exhibit somatic mutations, helping DNA restitution; 3. Somatic mutations in tumor cells aim for the restoration of DNA damage, rather than further genomic derangement; 4. In tumors, estrogen signaling drives the pathways of DNA stabilization, leading to apoptotic death; 5. In peritumoral cellular infiltration, the genomic damage of the tumor induces inflammatory cytokine secretion and increased estrogen synthesis. In the inflammatory cells, an increased growth factor receptor (GFR) signaling confers the unliganded activation of estrogen receptors (ERs); 6. In breast cancer cells responsive to genotoxic therapy, constitutive mutations help the upregulation of estrogen signaling and consequential apoptosis. In breast tumors non-responsive to genotoxic therapy, the possibilities for ER activation via either liganded or unliganded pathways are exhausted, leading to farther genomic instability and unrestrained proliferation.

Understanding the real character and behavior of human tumors at the molecular level suggests that we should learn the genome repairing methods of tumors and follow them by supportive therapy, rather than provoking additional genomic damages.

Glioblastoma multiforme (GBM) is a malignant tumor with a higher prevalence in men and a higher survival rate in transmenopausal women. It exhibits distinct areas influenced by changing environmental conditions. This study examines how these areas differ in the levels of estrogen receptors (ERs) which play an important role in the development and progression of many cancers, and whose expression levels are often correlated with patient survival. This study utilized two research models: an in vitro model employing the U87 cell line and a second model involving tumors resected from patients (including tumor core, enhancing tumor region, and peritumoral area). ER expression was assessed at both gene and protein levels, with the results validated using confocal microscopy and immunohistochemistry. Under hypoxic conditions, the U87 line displayed a decrease in ERβ mRNA expression and an increase in ERα mRNA expression. In patient samples, ERβ mRNA expression was lower in the tumor core compared to the enhancing tumor region (only in males when the study group was divided by sex). In addition, ERβ protein expression was lower in the tumor core than in the peritumoral area (only in women when the study group was divided by sex). Immunohistochemical analysis indicated the highest ERβ protein expression in the enhancing tumor area, followed by the peritumoral area, and the lowest in the tumor core. The findings suggest that ER expression may significantly influence the development of GBM, exhibiting variability under the influence of conditions present in different tumor areas.

Tamoxifen, a cornerstone in the adjuvant treatment of estrogen receptor-positive breast cancer, significantly reduces breast cancer recurrence and breast cancer mortality; however, its standard adjuvant dose of 20 mg daily presents challenges due to a broad spectrum of adverse effects, contributing to high discontinuation rates. Dose reductions of tamoxifen might be an option to reduce treatment-related toxicity, but large randomized controlled trials investigating the tolerability and, more importantly, efficacy of low-dose tamoxifen in the adjuvant setting are lacking. We conducted an extensive literature search to explore evidence on the tolerability and clinical efficacy of reduced doses of tamoxifen. In this review, we discuss two important topics regarding low-dose tamoxifen: (1) the incidence of adverse effects and quality of life among women using low-dose tamoxifen; and (2) the clinical efficacy of low-dose tamoxifen examined in the preventive setting and evaluated through the measurement of several efficacy derivatives. Moreover, practical tools for tamoxifen dose reductions in the adjuvant setting are provided and further research to establish optimal dosing strategies for individual patients are discussed.

Tamoxifen (TAM) resistance poses a significant clinical challenge in human breast cancer and exhibits high heterogeneity among different patients. Rg3, an original ginsenoside known to inhibit tumor growth, has shown potential for enhancing TAM sensitivity in breast cancer cells. However, the specific role and underlying mechanisms of Rg3 in this context remain unclear. Aerobic glycolysis, a metabolic process, has been implicated in chemotherapeutic resistance. In this study, we demonstrate that elevated glycolysis plays a central role in TAM resistance and can be effectively targeted and overcome by Rg3. Mechanistically, we observed upregulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key mediator of glycolysis, in TAM-resistant MCF-7/TamR and T-47D/TamR cells. Crucially, PFKFB3 is indispensable for the synergistic effect of TAM and Rg3 combination therapy, which suppresses cell proliferation and glycolysis in MCF-7/TamR and T-47D/TamR cells, both in vitro and in vivo. Moreover, overexpression of PFKFB3 in MCF-7 cells mimicked the TAM resistance phenotype. Importantly, combination treatment significantly reduced TAM-resistant MCF-7 cell proliferation in an in vivo model. In conclusion, this study highlights the contribution of Rg3 in enhancing the therapeutic efficacy of TAM in breast cancer, and suggests that targeting TAM-resistant PFKFB3 overexpression may represent a promising strategy to improve the response to combination therapy in breast cancer.