Treatment Of Breast Cancer Research Articles

Changes in blood metabolomes as potential biomarkers for severity and prognosis in doxorubicin-induced heart failure: a study in HER2-positive and HER2-negative breast cancer patients

Abstract Background The use of doxorubicin for breast cancer treatment is often limited due to cardiotoxicity. Doxorubicin was shown to cause the alterations of cardiac metabolome levels in doxorubicin-treated rats. Interestingly, these changes were robustly associated with the development of doxorubicin-induced heart failure. Unfortunately, measurements of cardiac metabolome levels are rarely possible in humans. Hence, non-invasive biomarkers as representatives of doxorubicin-induced heart failure are required in clinical research and practice. Human epidermal growth factor receptor 2 (HER2) is a point of interest in breast cancer treatment. HER2 is associated with tumor aggressiveness. However, it was observed that HER2 protected against systemic oxidative stress and dilated cardiomyopathy. Therefore, we hypothesized that the alterations of blood metabolome levels and cardiac functions following doxorubicin treatment were different between HER2-positive and HER2-negative breast cancer patients. Purpose We determined the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced heart failure. In addition, the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients were compared. Methods HER2-positive (n=37) and HER2-negative (n=37) breast cancer patients were enrolled. Echocardiography, heart rate variability, and blood collection were performed at baseline and 2 weeks after completion of doxorubicin treatment in all patients, as well as at 3 months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all 3 time points was processed for measuring cardiac injury markers. Blood obtained at baseline and 2 weeks after completion of doxorubicin treatment was also processed for measuring oxidative stress in peripheral blood mononuclear cells using flow cytometry and 85 metabolome levels in plasma using mass spectrometry-based targeted metabolomics. Results Cardiac injury and systolic dysfunction at 2 weeks after completion of doxorubicin treatment were comparable between HER2-positive and HER2-negative breast cancer patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2 weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively (Figure). Interestingly, the changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2 weeks and 3 months after completion of doxorubicin treatment (Figure). Conclusions The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, which might be served as severity and prognostic markers of doxorubicin-induced heart failure.

Incidence of cardiovascular diseases among breast cancer patients: a nationwide registry study 2013-2020

Abstract Background and aims There is evidence to suggest that breast cancer (BC) treatment is associated with an increased risk of developing cardiovascular disease (CVD). Several countries have introduced clinical measures to reduce the impact of breast cancer treatment on cardiovascular function including activated breathing control during radiotherapy, lower radiation doses, and maximum anthracycline doses. The overall aim of this study was therefore to investigate whether breast cancer patients still exhibit higher rates of cardiovascular disease than the general population. Methods We conducted a registry-based cohort study using linked data from four nationwide health registries. Out study population included all Norwegian patients diagnosed with BC between 2013-2020 and matched them by age to 10 controls without BC. Health outcomes were measured from 2008 to 2021. We estimated the cumulative incidence from index date, for ten selected CVDs. For BC patients, the index date was defined as date of BC diagnosis. For controls, the index date was defined as the date of BC diagnosis for the matched BC patient. A wash-out period of 5 years was applied to identify incident cases of CVD. Results The study population included 27,535 patients with BC and 269,9994 matched controls. Median age in both groups was 62 years (IQR: 20). Prior to index date, there were no significant differences in the prevalence of heart valve disease, chronic ischemic heart disease heart failure and peripheral vascular disease in BC patients compared to controls (p>0.05) (Table 1). Hypertensive heart disease, pulmonary embolism, atrial fibrillation, and other cardiac arrythmias were more prevalent in BC patients, while angina pectoris and acute myocardial infarction were more prevalent among controls. After the index date, the incidence proportion for heart valve disease, hypertensive heart disease, pulmonary embolism, atrial fibrillation, other cardiac arrythmias, and heart failure were higher in BC patients compared to controls (p<0.001) (Table 2). No significant differences were found for angina pectoris, acute myocardial infarction, chronic ischemic heart disease, and peripheral vascular disease. Conclusion Breast cancer is still associated with an increased risk of developing several CVDs in current clinical practice, compared to matched controls without breast cancer.Baseline characteristicsIncidence of CVD

Machine learning-guided synthesis of nanomaterials for breast cancer therapy

Breast cancer is a common malignant tumor, which mostly occurs in female population and is caused by excessive proliferation of breast epithelial cells. Breast cancer can cause nipple discharge, breast lumps and other symptoms, but these symptoms lack certain specificity and are easily confused with other diseases, thus affecting the early treatment of the disease. Once the tumor progresses to the advanced stage, distant metastasis can occur, leading to dysfunction of the affected organs, and even threatening the patients’ lives. In this study, we synthesized high drug-loading gel particles and applied them to control the release of insoluble drugs. This method is simple to prepare, cost-effective, and validates their potential in breast cancer therapy. We first characterized the morphology and physicochemical properties of gel loaded with newly synthesized compound 1 by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and thermal gravimetric analysis (TGA). Using newly synthesized insoluble compound 1 as a model drug, its efficacy in treating breast cancer was investigated. The results showed that hydrogel@compound 1 was able to significantly inhibit the proliferation, migration and invasion of breast cancer cells. Additionally, we utilized machine learning to screen three structurally similar compounds, which showed promising therapeutic effects, providing a new approach for the development of novel small-molecule drugs.

A Multicenter Physician Survey Evaluating the Use of Ki-67 in Breast Cancer Management in Canada

Background: Ki-67’s response to pre-operative endocrine therapy (ET) in early breast cancer is an evidence-based tool to guide adjuvant treatment decisions. Physicians across Canada were surveyed to explore current practice patterns and perceived barriers to the use of Ki-67 in practice. Methods: Physicians were invited to participate in an anonymous survey and were eligible if they prescribed systemic therapy for breast cancer in Canada. Respondents were asked to describe their usage of Ki-67, perceptions of the evidence surrounding Ki-67 ET response, and interest in future trials using this approach. Results: The survey received 48/163 responses (29.4%). The majority of respondents (97.6%) reported access to Ki-67 testing upon request. Treatment decisions for adjuvant Abemaciclib was the most common reason (97.6%), followed by adjuvant chemotherapy decisions (16.7%). Only 19.0% had used Ki-67’s response to pre-operative ET in practice. Common barriers to this approach that were identified included a lack of awareness from other providers (54.8%), an increased resource requirement (54.8%), and a lack of timely medical oncology consultation (52.4%). The majority of physicians (85.3%) reported that they would participate in future trials using the Ki-67 endocrine response, and that rate of treatment decision change (95.2%) and cost analysis (42.3%) were important endpoints. Conclusions: Despite the widespread availability of Ki-67 testing, few physicians in Canada currently use it to assess endocrine response, predominantly due to logistical and resource constraints. There is a high level of interest in participating in future trials using this strategy, which should focus on disease related outcomes, feasibility, and the financial impact on the public healthcare system.

Accelerated hazard prediction based on age time-scale for women diagnosed with breast cancer using a deep learning method

Breast cancer is the most common cancer in women. Previous studies have investigated estimating and predicting the proportional hazard rates and survival in breast cancer. This study deals with predicting accelerated hazards (AH) rate based on age categories in breast cancer patients using deep learning methods. The AH has a time-dependent structure whose rate changes according to time and variable effects. We have collected data related to 1225 female patients with breast cancer at the Mandarin University of Medical Sciences. The patients' demographic and clinical characteristics including family history, age, history of tobacco use, hysterectomy, first menstruation age, gravida, number of breastfeeding, disease grade, marital status, and survival status have been recorded. Initially, we dealt with predicting three age groups of patients: ≤ 40, 41–60, and ≥ 61 years. Then, the prediction of accelerated risk value based on age categories for each breast cancer patient through deep learning and the importance of variables using LightGBM is discussed. Improving clinical management and treatment of breast cancer requires advanced methods such as time-dependent AH calculation. When the behavioral effect is assumed as a time scale change between hazard functions, the AH model is more appropriate for randomized clinical trials. The study results demonstrate the proper performance of the proposed model for predicting AH by age categories based on breast cancer patients' demographic and clinical characteristics.

Validation of the HFA-ICOS risk assessment tool with real-world data from a prospective cohort of breast cancer patients in treatment with anthracyclines and trastuzumab

Abstract Background The increasing prevalence of cancer therapy-related cardiovascular toxicity (CTRCD) poses a significant challenge to patient management, necessitating accurate risk assessments. Previous methodologies have struggled with precise risk stratification, partly due to varying definitions of CTRCD and the specificity of cancer treatments. Purpose This study aimed to evaluate the assessment tool proposed by the Heart Failure Association and the International Cardio-Oncology Society (HFA-ICOS) in predicting the risk of CTRCD in patients undergoing anthracycline and trastuzumab treatment for breast cancer at a national reference center. Methods A prospective cohort study was conducted, encompassing 172 patients treated from January 2022 to July 2023. Patients were assessed at baseline, three months, and six months post-treatment initiation, with exclusion criteria including baseline left ventricular ejection fraction (LVEF) <50%, history of heart failure, and stage IV breast cancer. The study utilized the HFA-ICOS tool for risk stratification and CTRCD was defined with the current criteria of the European Society of Cardiology guideline. Descriptive statistics were calculated, and incidence rates and Cox proportional-hazards models were developed according to the risk category. Results In our study, 138 (80.2%) patients were classified as low risk, 23 (13.4%) as moderate risk and 11 (6.4%) as high risk. We identified 81 (47.1%) patients that developed CTRCD in follow-up. Descriptive characteristics can be found in Table 1. The global incidence rate for CTRCD in our cohort was of 2.4 new cases per 1000 person-days, however no differences in incidence rates were found when stratifying by risk category (Figure 1A). Moreover, patients with moderate to high risk according to the HFA-ICOS tool did not show a significantly increased hazard ratio for cardiotoxicity (HR 0.41, 95%CI 0.15-1.12, p=0.082 and HR 1.39, 95%CI 0.50-3.86, p=0.5, respectively) as shown in Figure 1B. Conclusion While the HFA-ICOS tool provides a structured framework for assessing cardiotoxicity risk, its predictive value in this cohort was limited. The findings underscore the complexity of cancer therapy-related cardiotoxicity and the need for enhanced, individualized risk assessment tools. Future research should focus on refining risk prediction models, incorporating broader clinical and genetic factors to improve patient outcomes in cardio-oncology.Table 1.Clinical CharacteristicsFigure 1.Incidence rates and Cox models

Comparison of two anthracycline regimens for treatment of breast cancer and the incidence of cardiac injury

Abstract Background Anthracycline based breast cancer treatment regimens have evolved over time. Whether the risk of myocardial injury is different between regimens is unclear. Purpose To compare the incidence and significance of high sensitivity troponin-I (TpI) levels immediately post anthracycline therapy in women with breast cancer treated with two different anthracycline regimens. Methods We prospectively recruited women with early-stage breast cancer who received either dose-dense doxorubicin and cyclophosphamide (ddAC) or 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) with or without subsequent HER2 therapy. The ddAC regimen comprises 4 cycles of doxorubicin given every 2 weeks (240mg/m2), whereas FEC consists of 3 cycles of epirubicin given every 3 weeks (total epirubicin dose of 300mg/m2, which is doxorubicin equivalent dose of 240mg/m2 using a cardiovascular toxicity dose ratio of 0.80 as per the 2022 ESC Cardio-oncology guidelines). Clinical characteristics were collected and TpI levels were measured before anthracyclines and 4-6 weeks post last dose. Comprehensive echocardiograms were conducted at baseline and post-therapy. Results 236 female participants were enrolled; 103 (43.6%) received ddAC and 133 (56.4%) received FEC. Compared to FEC, patients receiving ddAC were older (mean age 58.1±10.2 vs 51.0±9.3 years; p < 0.001) received similar cumulative doxorubicin equivalent dose (237.4±23.4 vs 239.9 ± 11.9 mg/m2; p=0.30), had similar baseline LVEF (62.1 ± 4.8 vs 61.3 ± 3.6%, p=0.14), and TpI levels (median (IQR) 2.0 (2.0-2.0) vs 2 (2.0-3.0) ng/L, p=0.12) respectively. Baseline risk factors were similar (hypertension 21% vs 17%, p=0.34; diabetes 7% vs 5%, p=0.44; dyslipidemia 15% vs. 8%, p=0.12). Post-anthracycline, the ddAC group had higher TpI level compared to patients in the FEC group (median (IQR) 12 (7-29) vs 6 (4-11) ng/L; p<0.001). The proportion of patients with abnormal TpI levels (>99th percentile, >16.0 ng/L) was higher in the ddAC group (43.7% vs 15.0%; p < 0.001). In a multivariable linear regression model that included age, treatment regimen, baseline TpI, hypertension, diabetes mellitus and dyslipidemia, ddAC remained significantly associated with higher post anthracycline TpI levels (β=15.5, 95%CI: 8.7-22.3; p<0.001). There was no significant difference in the mean LVEF post-anthracycline (59.9 ± 5.1 vs 60.0 ± 3.8; p=0.91). No patients developed clinical heart failure. Conclusion Despite similar doxorubicin equivalent doses, the incidence of abnormal TpI levels was ~3 fold higher with DD-AC than FEC. Given that DD-AC is now more commonly used especially with immunotherapy this knowledge is clinically relevant. The difference in proportion with troponin elevation could be due to differences in the number of cycles (3 vs 4) and the frequency of chemotherapy administration (every 2 vs 3 weeks) between the regimens. However, this did not translate into a larger reduction in LVEF. But longer-term follow-up is needed.

Development of Stable and Intensified Mixing Processes for the Precise and Scalable Production of Uniform Drug Delivery Nanocarriers.

Nanocarriers show great promise in drug delivery but face challenges in stability, uniformity, and morphology control. This work introduces an enhanced mixing process to overcome these obstacles, specifically aiming to produce consistently sized poly(lactic-co-glycolic) acid (PLGA) nanoparticles loaded with anti-tumor drugs. By innovatively integrating a pulsation dampener into the microfluidic channels of a continuous flow preparation system, the flow stability of piston pumps is improved nearly tenfold. Consequently, large-scale production of uniformly sized nanoparticles with customizable dimensions is achieved through nanoprecipitation. Furthermore, incorporating terminal double-bond-functionalized poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-maleimide (PLGA-PEG-Mal) enables these nanoparticles to act as nano-crosslinkers. This facilitates in situ crosslinking with thiolated hyaluronic acid via a spontaneous thiol-ene coupling reaction under physiological conditions, allowing for minimally invasive drug administration and significantly enhancing localized drug retention. The material's degradability in the presence of endogenous enzymes ensures controlled drug release, as demonstrated with the anti-tumor drug doxorubicin (DOX). Validation in a murine breast cancer model shows reduced toxicity and a substantial reduction in tumor weight compared to the free DOX group. These findings confirm the approach's effectiveness for breast cancer treatment and pave the way for innovative solutions in nanomedicine, providing a practical microfluidic mixing system for the design and large-scale production of nanomedicines.

An interpretable deep learning model for detecting BRCA pathogenic variants of breast cancer from hematoxylin and eosin-stained pathological images.

Determining the status of breast cancer susceptibility genes (BRCA) is crucial for guiding breast cancer treatment. Nevertheless, the need for BRCA genetic testing among breast cancer patients remains unmet due to high costs and limited resources. This study aimed to develop a Bi-directional Self-Attention Multiple Instance Learning (BiAMIL) algorithm to detect BRCA status from hematoxylin and eosin (H&E) pathological images. A total of 319 histopathological slides from 254 breast cancer patients were included, comprising two dependent cohorts. Following image pre-processing, 633,484 tumor tiles from the training dataset were employed to train the self-developed deep-learning model. The performance of the network was evaluated in the internal and external test sets. BiAMIL achieved AUC values of 0.819 (95% CI [0.673-0.965]) in the internal test set, and 0.817 (95% CI [0.712-0.923]) in the external test set. To explore the relationship between BRCA status and interpretable morphological features in pathological images, we utilized Class Activation Mapping (CAM) technique and cluster analysis to investigate the connections between BRCA gene mutation status and tissue and cell features. Significantly, we observed that tumor-infiltrating lymphocytes and the morphological characteristics of tumor cells appeared to be potential features associated with BRCA status. An interpretable deep neural network model based on the attention mechanism was developed to predict the BRCA status in breast cancer. Keywords: Breast cancer, BRCA, deep learning, self-attention, interpretability.

Development of a cardiotoxicity evaluation system using a Heart-on-a-Chip Microdevice with aligned fiber device

Abstract Background and Purpose Cardiovascular cells differentiated from human induced pluripotent stem (iPS) cells, such as cardiomyocytes, are expected to be useful for evaluating cardiac pharmacology and toxicity in humans. In recent years, myocardial damage caused by anticancer drugs has begun to attract attention. Being able to evaluate human cardiotoxicity early in the development of novel drugs like anticancer agents confers advantages in terms of cost and development speed. The aim of this study was to develop a highly sensitive bioassay system that can evaluate the physiological function of the human heart, and to validate the efficacy of the system toward detection of cardiotoxicity of drugs. Methods We differentiated human iPS cells into cardiovascular cells (cardiomyocytes, endothelial cells and mural cells) and applied dynamic culture training to generate vascularized microtissues (VCM) with vascular network structures. By integrating this VCM with a microfluidic chip containing microchannels, we developed a heart-on-a-chip microdevice (HMD) specialized for evaluating cardiac function (Figure 1). Furthermore, through a collaborative study with the Stem Cell & Device Laboratory (SCAD), application of their aligned fiber device improved throughput and stability, allowing development of a SCAD-HMD capable of evaluating longer-term cardiotoxicity. Results SCAD-HMD can quantify physiological parameters of VCM such as ejection volume and force based on displacement of particles within the microchannels. Our results showed that SCAD-HMD not only exhibited pharmacological responses to representative circulatory stimulants, but also reproduced clinical events occurring in actual practice, demonstrating that the anticancer drug trastuzumab, commonly used for breast cancer treatment, causes myocardial disfunction when combined with doxorubicin. Conclusions This study demonstrated that SCAD-HMD can stably evaluate the toxicity of drugs on the human heart. In the future, establishing SCAD-HMD using iPS cells derived from individual patients and assessing responses to specific drugs may enable "individualized cardiotoxicity assessment systems" that can preemptively avoid cardiac complications associated with anticancer drugs and other pharmacological agents.

The effects of Tai Chi and Baduanjin on breast cancer patients: systematic review and meta-analysis of randomized controlled trials

BackgroundTai Chi and Baduanjin are nonpharmacological interventions that are widely applied among cancer patients.ObjectiveThis meta-analysis aimed to assess the effect of Tai Chi and Baduanjin on breast cancer patients by summarizing and pooling the results of previous studies.MethodsThe PubMed, Embase, Web of Science, Scopus and Cochrane Library and several databases were searched up to December 1, 2023, to identify high-quality RCTs. Relevant terms such as Tai Chi and Baduanjin were used as keywords. Stata 15.0 software and Review Manager (version 5.3; Cochrane Training) were used to screen the studies, extract the data, code the data, and perform the meta-analysis. The mean differences (MDs) and standardized mean differences (SMDs) with 95% CIs were used to calculate continuous variables. The Cochrane risk of bias assessment tool was used to evaluate the risk of bias. The PICOS framework was used to develop the following eligibility criteria: (i) population - breast cancer patients; (ii) intervention - Tai Chi and Baduanjin intervention; (iii) comparison - Tai Chi and Baduanjin group and different intervention (e.g., regular intervention, routine rehabilitation training, waiting list, sham Qigong, usual care, no intervention); (iv) outcomes - cognitive ability, shoulder joint function, anxiety, depression, fatigue, sleep quality, quality of life; and (v) study design - randomized controlled trial.ResultsFrom January 2013 to December 2023, we included a total of 16 RCTs involving 1247 patients. A total of 647 patients were in the experimental group and were treated with Tai Chi and Baduanjin, while 600 patients were in the control group and were treated with traditional methods. The results of our meta-analysis indicate that Tai Chi and Baduanjin yield outcomes that are comparable to those of traditional treatment methods. Specifically, Tai Chi and Baduanjin significantly increased cognitive function, increased shoulder joint function, improved sleep quality indicators and improved quality of life indicators. Furthermore, Tai Chi and Baduanjin significantly reduced anxiety symptoms, depression symptoms, and fatigue symptoms among breast cancer patients. Sensitivity analysis was performed, a funnel plot was constructed. No publication bias was indicated by Egger’s or Begg’s test.ConclusionOverall, Tai Chi and Baduanjin are viable and effective nonpharmacological approaches for treating breast cancer patients, as they yield better results than traditional treatment methods. However, these findings should be interpreted with caution due to the limited number of controlled trials, small sample sizes, and low quality of the evidence.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023469301.

Synergistic Anti-Tumor Effects of Newcastle Disease Virus and Doxorubicin: Evidence from A Murine Breast Cancer Model

BackgroundDespite the recent advances in the diagnosis and treatment of breast cancer, triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive nature and resistance to conventional therapies. Virotherapy has emerged as a promising cancer treatment strategy, leveraging the ability of viruses to specifically target and replicate in cancerous cells. This study evaluated the oncolytic potential of a combined therapeutic strategy, utilizing Newcastle disease virus (NDV) and Doxorubicin hydrochloride (Dox) both in vitro and in vivo. MethodsThe in vitro experiments involved exposing human and mouse TNBC cell lines (MDA-MB-231 and 4T1, respectively) to NDV and Dox, individually or in combination. Cell viability assays and flow cytometry analyses were conducted to assess the synergistic effects of NDV and Dox on regulating breast cancer cell behavior in vitro. Furthermore, the immune-stimulating potential of NDV was investigated by examining its effects on dendritic cell (DC) maturation using flow cytometry and T cell proliferation. The in vitro anti-tumor effects of NDV were examined in both parental and tamoxifen-resistant cancer cells to assess its efficacy against chemoresistance. Animal models of breast cancer were treated with NDV in combination with Dox. The body weight changes, tumor volume, and survival rates of the mice were monitored throughout the study. Histopathological analyses were conducted to evaluate the potential toxic effects of the treatments. ResultsBased on the MTT results, NDV at optimal concentrations synergized the effect of Dox to reduce the viability of both MDA-MB231 and 4T1 cell lines (Isobologram combination index of less than 1). Additionally, individual treatment with NDV was able to significantly reduce the viability of patient-derived breast cancer cells, compared to the untreated control (P < 0.05) without affecting the cells of normal adjacent tissue. Furthermore, a combination of NDV and Dox significantly enhanced the percentage of early and late apoptotic cells in MDA-MB-231 (P < 0.0001) and late apoptotic cells in 4T1 (P < 0.0001), in comparison with individual treatment with these agents. Flow cytometry results showed that, compared to wild type MDA-MB-231 cells, NDV-infected MDA-MB-231 cells were better inducers of T cell proliferation and DC maturation as evidenced by increased proliferation index (P < 0.05) and elevated expression of CD1a, CD83, and CD86 (P < 0.0001), respectively. Moreover, co-treatment of both wild-type and (tamoxifen) TAM-resistant MCF-7/TAMR-1 cells with TAM and NDV significantly reduce the viability of the cancer cells (P < 0.0001). In tumor-bearing mice locally engrafted with 4T1 cells, combined treatment of NDV and Dox exhibited a marked reduction in median tumor volume compared to the control group, validating our in vitro findings on their synergistic anti-tumor effects. These findings suggest that combining NDV with Dox can effectively inhibit tumor progression and has the potential to reduce the dose, and consequently the toxic side-effects, of Dox in breast cancer therapy.

Anti-neoplastic Effects of Juglans Regia L. Green Fruit Pericarp on Breast Cancer Cell Lines

Background: Recently, more attention has been paid to the use of complementary medicine in breast cancer (BC) treatment. Juglans green fruit pericarp was found to have anti-cancer characteristics. Objectives: We aimed here to assess the possible anti-proliferative effects of methanolic extract of Juglans green fruit pericarp in BC cell lines. Methods: MCF-7 and MDA-MB-231 cells were examined with different concentrations of Juglans green fruit pericarp extract. The cell viability was investigated using a 3 - 2, 5-diphenyl tetrazolium bromide (MTT) assay. Also, different phases of the cell cycle were analyzed utilizing a flow cytometry method. Finally, the ability of cancer cells to create colonies was studied post-treatment with Juglans green fruit pericarp. Results: Our findings showed that the methanol extract has substantial cytotoxicity on MCF-7 and MDA-MB-231 cell lines. We also observed a significant arrest in the G0/G1 phase in cancer cells post-treatment with the methanol extract. Conclusions: In summary, our results introduced a cytotoxic property for Juglans green fruit pericarp methanol extract for MCF-7 and MDA-MB-231 cell lines. Future studies are needed to further evaluate its utility as a potential complementary therapy for BC.

The Growth Inhibition Effect of Different Extracts of Taraxacum Peregrinum Leaves on Breast Cancer Cell Line MDA-MB-468

Background and Objectives: The dandelion plant (Taraxacum officinale) is one of the plants with beneficial effects. In this study, we evaluated the growth inhibition of different extracts of Iranian dandelion (Taraxacum peregrinum) on breast cancer cells. Methods: Ethanolic, methanolic, hydroalcoholic, and aqueous extracts and juice of dandelion leaves were first prepared by the Maceration method. Seven concentrations (0.01, 0.1, 1, 10, 100, 1000, and 10000 mg/mL) were prepared from different extracts. Cisplatin was used as a standard anticancer drug. Their half-maximal inhibitory concentration (IC50) values were evaluated by the MTT assay. Data analysis was done in Excel and GraphPad Prism 8.0.2 software. Results: By increasing the concentration of different extracts, the growth inhibitory effect on cancerous cells increased after 72 hours of exposure. The greatest growth inhibition effect was shown by ethanolic extract (IC50=0.75±0.31 mg/mL) after 72 hours of exposure followed by methanolic extract (IC50=6.25±0.76 mg/mL) and aqueous extract (IC50=6.59±0.94 mg/mL). Their effects were much more significant and better than Cisplatin (IC50=42.57±1.73 mg/mL). However, hydroalcoholic extract and juice of dandelion leaf did not show a significant growth inhibition effect. Conclusion: Given the significant effects of ethanolic, methanolic, and aqueous extracts of Taraxacum peregrinum leaves on inhibiting the growth of the MDA-MB-468 breast cancer cell line, this plant can be used as an herbal supplement for the treatment of breast cancer.

Curcumin Administration Routes in Breast Cancer Treatment

Breast cancer is a public health concern worldwide, characterized by increasing incidence and mortality rates, requiring novel and effective therapeutic strategies. Curcumin is a bioactive compound extracted from turmeric with several pharmacological activities. Curcumin is a multifaceted anticancer agent through mechanisms including the modulation of signaling pathways, inhibition of cell proliferation, induction of apoptosis, and production of reactive oxygen species. However, the poor water solubility and bioavailability of curcumin create important barriers in its clinical application. This review elaborates on the therapeutic potential of curcumin in breast cancer treatment, focusing on the efficacy of different administration routes and synergistic effects with other therapeutic agents. The intravenous administration of curcumin-loaded nanoparticles significantly improves bioavailability and therapeutic outcomes compared to oral routes. Innovative formulations, such as nano-emulsifying drug delivery systems, have shown promise in enhancing oral bioavailability. While intravenous delivery ensures higher bioavailability and direct action on tumor cells, it is more invasive and expensive than oral administration. Advancing research on curcumin in breast cancer treatment is essential for improving therapeutic outcomes and enhancing the quality of life of patients.

CDK4/6 inhibition initiates cell cycle arrest by nuclear translocation of RB and induces a multistep molecular response

CDK4/6 inhibitors are standard of care in the treatment of metastatic breast cancer. Treatment regimen consists of a combination with endocrine therapy, since their therapeutic efficacy as monotherapy in most clinical trials was rather limited. Thus, understanding the molecular mechanisms that underlie response to therapy might allow for the development of an improved therapy design. We analyzed the response to the CDK4/6 inhibitor palbociclib in bladder cancer cells over a 48-hour time course using RNA sequencing and identified a multi-step mechanism of response. We next translated these results to the molecular mechanism in bladder cancer cells upon PD treatment. The initial step is characterized by translocation of the RB protein into the nucleus by activation of importin α/β, a mechanism that requires the NLS sequence. In parallel, RB is proteolyzed in the cytoplasm, a process regulated by gankyrin and the SCF complex. Only hypophosphorylated RB accumulates in the nucleus, which is an essential step for an efficient therapy response by initiating G1 arrest. This might explain the poor response in RB negative or mutated patients. At later stages during therapy, increased expression of the MiT/TFE protein family leads to lysosomal biogenesis which is essential to maintain this response. Lastly, cancer cells either undergo senescence and apoptosis or develop mechanisms of resistance following CDK4/6 inhibition.

Understanding the chemistry & pharmacology of antibody-drug conjugates in triple-negative breast cancer with special reference to exatecan derivatives.

In the spectrum of breast malignancies, triple-negative breast cancer is the most widely spreading subtype of breast cancer due to a low availability of therapeutic remedies. Recently, antibody-drug conjugates dramatically resolved the landscape for the treatment of triple-negative breast cancer. This review mainly focuses on the chemistry, structure, mechanism of action, and role of antibody-drug conjugates in triple-negative breast cancer. Datopotecan Deruxtecan (Dato-DXd) is a new-generation ADC showing encouraging results for TNBC. In this review, we have also emphasized TROP-2-directed Datopotamab deruxtecan ADCs to treat triple-negative breast cancer, its synthesis, mechanism of action, pharmacokinetics, pharmacodynamics, adverse events, and their ongoing clinical trials.

Profiling Breast Tumor Heterogeneity and Identifying Breast Cancer Subtypes Through Tumor-Associated Immune Cell Signatures and Immuno Nano Sensors.

Breast cancer is a complex and heterogeneous disease with varying cellular, genetic, epigenetic, and molecular expressions.The detection of intratumor heterogeneity in breast cancer poses significant challenges due to its complex multifaceted characteristics, yet its identification is crucial for guiding effective treatment decisions and understanding the diseaseprogression. Currently, there exists no method capable of capturing the full extent of breast tumor heterogeneity. In this study, the aim is to identify and characterize metabolic heterogeneity in breast tumors using immune cells and an ultrafast laser-fabricated Immuno Nano Sensor.Combining spectral markers from both Natural Killer (NK)and T cells, a machine-learning approach is implemented to distinguish cancer from healthy samples, identify primary versus metastatic tumors, and determine estrogen receptor (ER)/progesterone receptor (PR) status at the single-cell level. The platform successfully distinguished heterogeneous breast cancer samples fromhealthy individuals, achieving97.8%sensitivity and92.2%specificity, andaccurately identifiedprimary tumors from metastatic tumors. Characteristic spectral signatures allow for discrimination between ER/PR-positive andnegative tumors with 97.5% sensitivity.This study demonstrates the potential of immune cell-based metabolic profiling in providing a comprehensive assessment of breast tumor heterogeneity and paving the way for minimally invasive liquid biopsy approaches in breast cancer diagnosis and management.

Transcriptional factor KLF9 overcomes 5-fluorouracil resistance in breast cancer via PTEN-dependent regulation of aerobic glycolysis

The emergence of resistance to 5-Fluorouracil (5-FU) is a staple in breast cancer chemotherapy. This paper delves into the role of PTEN in breast cancer resistance to 5-FU and examines the underlying molecular pathways. PTEN expression was detected in bioinformatics databases and upstream transcription factors (TFs) were identified. PTEN mRNA and protein levels, aerobic glycolysis proteins, lactate production, glucose consumption, and cell viability were measured. Binding interactions were confirmed, and cell proliferation assessed. In breast cancer cells, PTEN expression was downregulated. PTEN overexpression counteracted 5-FU resistance through the suppression of aerobic glycolysis. KLF9, as a TF upstream of PTEN, enhanced the levels of PTEN. In conclusion, the TF KLF9 inhibits the aerobic glycolysis level of breast cancer cells by up-regulating PTEN expression, thereby reducing their resistance to 5-FU. The discovery of this mechanism provides a new theoretical basis for the treatment of breast cancer.

Molecular Simulation and Impact of Solvent‐Based Analysis of 2‐Methoxy‐4‐Allylphenol (Eugenol) Targeting Progesterone Receptor for Breast Cancer Therapy

ABSTRACTBreast cancer is a leading cause of cancer‐related morbidity and mortality among women globally. It arises from the abnormal proliferation of cells within breast tissue and can manifest in several subtypes, classified by the expression of hormone receptors. The main objective of this work is to assess the effect of solvent on 2‐methoxy‐4‐allylphenol's (2M4AP) in quantum chemical calculations and ability of 2M4AP to bind with the proteins associated with breast cancer. The non‐toxic nature of 2M4AP was initially validated through drug‐likeness studies and it complies with Lipinski's criteria. The optimization of 2M4AP structure was carried out in gas and liquid phase in DFT technique with B3LYP/6‐311++G (d, p) level. Then the electronic spectrum was calculated in TD‐DFT technique and the transition was determined to be n → σ*. The steadiness, charge dispersal and electronic properties were assessed and the band energy value was calculated to be 5.58 eV (gas) and 5.64 eV (liquid), exhibiting a stable confirmation of 2M4AP structure. Topological characteristics exhibited the intermolecular connections of 2M4AP along with electronic features. From the simulated results, the effect of solvent (water) in 2M4AP was very minimal and the structure is stable in both gas and liquid phase. Further, the docking studies, 2M4AP exhibited highest binding score of −7.3 kcal/mol with progesterone receptor, confirming the better ability of 2M4AP to react in hormone‐positive breast cancer. The Ramachandran plot confirms the stability of interacted amino acids with the ligand molecule. Thus, 2M4AP can be considered as a potent candidate for treatment of breast cancer after clinical studies.