Knockdown of NUF2-derived exosomes can inhibit the migration and autophagy of BC cells and improve resistance to doxorubicin.

Breast cancer (BC) is the most common type of fatal cancer in women. New therapeutic strategies need to be explored to enhance the efficacy of doxorubicin by overcoming the resistance of BC cells. NUF2 is a component of the Ndc80 centromere complex and is a key substance in mediating mitosis and affects the progression of multiple tumors. However, the role as well as mechanisms of NUF2 resistance in BC remain unclear. This study aims to reveal the role of NUF2 in drug resistance in BC. We here revealed that NUF2 was highly expressed in human BC. NUF2 depletion-derived exosomes blocked the growth of BC cells. Further, NUF2 ablation-derived exosomes inhibited autophagy in BC cells. Also, NUF2 ablation-derived exosomes improved doxorubicin resistance in BC cells. Mechanically, NUF2 ablation-derived exosomes blocked PI3K/AKT/mTOR axis in BC cells. In summary, NUF2 ablation-derived exosomes blocked the autophagy of BC cells and improved doxorubicin resistance via mediating PI3K/AKT/mTOR axis.

Screening of postoperative adjuvant chemotherapy-related serum metabolic markers in breast cancer patients based on 1H NMR metabonomics.

Background: Breast cancer (BC) has the highest incidence rate among female malignant tumors. Adjuvant chemotherapy is commonly used to reduce micrometastasis in postoperative patients. However, monitoring the efficacy of chemotherapy in BC is a major challenge in clinical practice. In this study, 1H nuclear magnetic resonance (NMR) metabonomics was performed to explore the serum metabolic characteristics of BC patients before and after adjuvant chemotherapy. Methods: In this study, we collected serum samples from 51 healthy controls and 61 BC patients before and after chemotherapy for 1H NMR metabolomic analysis, and tested the performance of each metabolite and combination segment by the receiver operating characteristic (ROC) curves. Results: Nine metabolites, namely glutamine, citrate, creatine, glycerophosphatidylcholine/phosphatidylcholine, glycine, 1-methylhistidine, lactate, pyruvate and formate had significant changes in BC patients before chemotherapy compared with healthy controls. Lactate, pyruvate, 1-methylhistidine and formate were found to be inversely regulated by chemotherapy. ROC analysis showed that a combination of the four metabolites had good prediction for chemotherapy efficacy with area under the curve of 0.958, sensitivity of 98.36% and specificity of 91.30%. There was no significant correlation between chemotherapy-related metabolites and clinical indicators of cancer patients, indicating that they can be used to evaluate the chemotherapy efficacy of patients with different clinical indicators. Conclusions: Effectively, dynamic and non-invasive metabolic markers for the evaluation of the efficacy of chemotherapy were identified in this study.

Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition.

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.

Establishment of a logistic regression model nomogram for clinicopathological characteristics and risk factors with axillary lymph node metastasis in T1 locally advanced breast cancer: a retrospective study.

Background: Although the research reports on locally advanced breast cancer (LABC) are increasing year by year, there are few reports on T1 LABC axillary lymph node metastasis (ALNM). By establishing a prediction model for T1 LABC ALNM, this study provides a reference value for the probability of ALNM of related patients, which helps clinicians to develop a more effective and individualized treatment plan for LABC. Methods: Cases with pathologically confirmed T1 breast cancer (BC) between 2010 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were identified. Logistic regression was used to analyze the correlation between LABC lymph node metastasis and every factor, and the odds ratio (OR) and 95% confidence interval (CI) were used to identify any influencing factors. A nomogram was drawn after incorporating meaningful factors identified in multivariate logistic regression into the model. The receiver operating characteristic (ROC) curve of the model was drawn, and the area under the curve (AUC) and its 95% CI were calculated. Hosmer-Lemeshow goodness-of-fit test and clinical decision curve analysis (DCA) were performed. The results were validated in the validation group. Results: A total of 200,933 female T1 BC patients were included in this study. Univariate and multivariate logistic regression analysis of T1 BC showed that progesterone receptor (PR)-negative, race, age, lobular carcinoma, micropapillary ductal carcinoma, axillary tail tumor, poor differentiation, and larger tumor diameter increased the probability of ALNM in T1 LABC. A predictive nomogram was established using the above predictors, the AUC of the modeling group was 0.739 (95% CI: 0.732-0.747), and when the AUC cut-off value was 0.026, the specificity and sensitivity of the model were 65.78% and 69.99%, respectively. Validation of the model showed that the AUC of the validation group (n=60,280) was 0.741. When all the risk factors were met, the predicted probability of N2-N3 was 50.40%. Conclusions: In this study, it was found that PR-negative, Black race, age, lobular carcinoma, micropapillary ductal carcinoma, axillary tail tumor, poor differentiation, and tumor diameter increased the probability of large lymph node metastasis in T1 LABC small tumors.

Rat Models of Hormone Receptor-Positive Breast Cancer.

Hormone receptor-positive (HR+) breast cancer (BC) is the most common type of breast cancer among women worldwide, accounting for 70-80% of all invasive cases. Patients with HR+ BC are commonly treated with endocrine therapy, but intrinsic or acquired resistance is a frequent problem, making HR+ BC a focal point of intense research. Despite this, the malignancy still lacks adequate in vitro and in vivo models for the study of its initiation and progression as well as response and resistance to endocrine therapy. No mouse models that fully mimic the human disease are available, however rat mammary tumor models pose a promising alternative to overcome this limitation. Compared to mice, rats are more similar to humans in terms of mammary gland architecture, ductal origin of neoplastic lesions and hormone dependency status. Moreover, rats can develop spontaneous or induced mammary tumors that resemble human HR+ BC. To date, six different types of rat models of HR+ BC have been established. These include the spontaneous, carcinogen-induced, transplantation, hormone-induced, radiation-induced and genetically engineered rat mammary tumor models. Each model has distinct advantages, disadvantages and utility for studying HR+ BC. This review provides a comprehensive overview of all published models to date.

Shoulder function following oncoplastic breast conserving surgery-a narrative review.

Background and Objective: The high prevalence of breast cancer survivors makes it very relevant to investigate late morbidity following the treatment. Oncoplastic breast conserving surgery (OPS) has gained great popularity over the past years, and evidence-based knowledge suggest better prognosis for treatment with breast conserving surgery (BCS) compared to mastectomy. The aim was to investigate if OPS causes late effects on an acceptable level compared to what we know about breast surgery causing late effects. Methods: Using the Medical Subject Headings (MeSH) terms "Breast Neoplasms", "shoulder", "oncoplast*", and "reconstruct*", the databases PubMed, Embase, and Scopus were searched on the 6th of June 2023. The literature search was managed in Covidence. We focused on studies describing late effects especially shoulder function including restrictions in mobility, reduced strength, as well as functional impairment. Key Content and Findings: Nine studies fulfilled the inclusion criteria. Different kinds of oncoplastic procedures were described-most of them described volume replacement procedures. The knowledge of shoulder morbidity following OPS is limited. The heterogeneity in the selected studies was broad. Some of the studies were small and there was a considerable variation in follow-up time. They described shoulder function based on several different evaluation methods [range of motion (ROM), Disabilities of the Arm, Shoulder, and Hand (DASH), Quick-DASH (Q-DASH), Shoulder Pain and Disability Index (SPADI), health-related quality of life (HRQoL), and non-validated subjective questionnaires]. All studies found acceptable levels of shoulder morbidity. Conclusions: The requisite knowledge of late effects following OPS is still not available for unambiguous recommendations. This narrative review has elucidated the knowledge and has reached a conclusion based on review of the existing literature of this item. We found that the risk of decreased shoulder function caused by OPS-volume displacement as well as volume replacement-does not exceed the risk of shoulder problems seen after BCS and mastectomy with or without immediate reconstruction. Therefore, OPS can be considered if conventional BCS is not possible. But the knowledge of shoulder function after OPS is limited, and studies comparing shoulder function after OPS, BCS and mastectomy with or without immediate reconstruction are warranted.

Evaluating the added value of synthetic magnetic resonance imaging in predicting sentinel lymph node status in breast cancer.

Background: The noninvasive prediction of sentinel lymph node (SLN) metastasis using quantitative magnetic resonance imaging (MRI), particularly with synthetic MRI (syMRI), is an emerging field. This study aimed to explore the potential added benefits of syMRI over conventional MRI and diffusion-weighted imaging (DWI) in predicting metastases in SLNs. Methods: This retrospective study consecutively enrolled 101 patients who were diagnosed with breast cancer (BC) and underwent SLN biopsy from December 2022 to October 2023 at the Affiliated Hospital of Jiangnan University. These patients underwent preoperative MRI including conventional MRI, DWI, and syMRI and were categorized into two groups according to the postoperative pathological results: those with and without metastatic SLNs. MRI morphological features, DWI, and syMRI-derived quantitative parameters of breast tumors were statistically compared between these two groups. Binary logistic regression was used to separately develop predictive models for determining the presence of SLN involvement, with variables that exhibited significant differences being incorporated. The performance of each model was evaluated through receiver operating characteristic (ROC) curve analysis, including the area under the curve (AUC), sensitivity, and specificity. Results: Compared to the group of 54 patients with BC but no metastatic SLNs, the group of 47 patients with BC and metastatic SLNs had a significantly larger maximum axis diameter [metastatic SLNs: median 2.40 cm, interquartile range (IQR) 1.50-3.00 cm; no metastatic SLNs: median 1.80 cm, IQR 1.37-2.50 cm; P=0.03], a higher proton density (PD) (78.44±11.92 vs. 69.20±10.63 pu; P<0.001), and a lower apparent diffusion coefficient (ADC) (metastatic SLNs: median 0.91×10-3 mm2/s, IQR 0.79-1.01 mm2/s; no metastatic SLNs: median 1.02×10-3 mm2/s, IQR 0.92-1.12 mm2/s; P=0.001). Moreover, the prediction model with maximum axis diameter and ADC yielded an AUC of 0.71 [95% confidence interval (CI): 0.618-0.802], with a sensitivity of 78.72% and a specificity of 51.85%; After addition of syMRI-derived PD to the prediction model, the AUC increased significantly to 0.86 (AUC: 0.86 vs. 0.71; 95% CI: 0.778-0.922; P=0.002), with a sensitivity of 80.85% and a specificity of 81.50%. Conclusions: Combined with conventional MRI and DWI, syMRI can offer additional value in enhancing the predictive performance of determining SLN status before surgery in patients with BC.

Circulating tumor cells et al.: towards a comprehensive liquid biopsy approach in breast cancer.

Liquid biopsy has emerged as a crucial tool in managing breast cancer (BC) patients, offering a minimally invasive approach to detect circulating tumor biomarkers. Until recently, the majority of the studies in BC focused on evaluating a single liquid biopsy analyte, primarily circulating tumor DNA and circulating tumor cells (CTCs). Despite the proven prognostic and predictive value of CTCs, their low abundance when detected using enrichment methods, especially in the early stages, poses a significant challenge. It is becoming evident that combining diverse circulating biomarkers, each representing different facets of tumor biology, has the potential to enhance the management of patients with BC. This article emphasizes the importance of considering these biomarkers as complementary/synergistic rather than competitive, recognizing their ability to contribute to a comprehensive disease profile. The review provides an overview of the clinical significance of simultaneously analyzing CTCs and other biomarkers, including cell-free circulating DNA, extracellular vesicles, non-canonical CTCs, cell-free RNAs, and non-malignant cells. Such a comprehensive liquid biopsy approach holds promise not only in BC but also in other cancer types, offering opportunities for early detection, prognostication, and therapy monitoring. However, addressing associated challenges, such as refining detection methods and establishing standardized protocols, is crucial for realizing the full potential of liquid biopsy in transforming our understanding and approach to BC. As the field evolves, collaborative efforts will be instrumental in unlocking the revolutionary impact of liquid biopsy in BC research and management.

Challenges in HER2-low breast cancer identification, detection, and treatment.

Recently, human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) has emerged as a novel subset within the category of HER2-negative BC, prompting a reassessment of the immunohistochemical negative scores of 0, 1+, and the 2+/in situ hybridization (ISH) negative phenotype. Recent clinical trials have provided compelling evidence of the substantial clinical advantages offered by novel antibody-drug conjugates (ADCs) that target HER2 in the treatment of these specific tumor cohorts. Notably, trastuzumab deruxtecan (T-Dxd), an ADC that specifically targets HER2, has recently received approval from the US Food and Drug Administration as the inaugural targeted therapeutic option for HER2-low BC. However, the classification of HER2-low BC as a distinct subtype, the methods for detecting HER2-low BC, and the optimal treatment approach for HER2-low BC remain subjects of ongoing debate and lack consensus. This comprehensive review aims to address these pertinent concerns, offering insights into the nuanced tumor biology underlying HER2-low BC and critically analyzing the current treatment pathways available. By synthesizing available evidence, the objective is to contribute to an enhanced understanding of HER2-low BC, providing a foundation for more informed clinical decisions and further advancements in tailored therapeutic approaches. As the medical community navigates these uncertainties, this review seeks to consolidate existing knowledge, fostering a collective effort toward establishing consensus in the diagnosis and treatment of HER2-low BC.

Expert consensus on the clinical application of immunotherapy in breast cancer: 2024.

Background: Significant progress has been made in immunotherapy of breast cancer (BC) with the approval of multiple immune checkpoint inhibitors (ICIs), particularly in early and metastatic triple-negative breast cancer (TNBC) settings. Most guidelines have recommended immune therapy as the important approach in BC, yet several critical aspects still require further clarification, including proper patient selection, treatment duration, optimized chemotherapy partner, predictive biomarkers, and specific considerations for Chinese patients. Methods: (I) Establishment of expert group: the expert group consists of 32 experts from departments such as medical oncology, breast surgery, and pathology; (II) literature search: mainly conducted in English databases (such as PubMed, Embase, and Cochrane Library) and Chinese databases (such as China National Knowledge Infrastructure, China Biology Medicine disc, and Wanfang Database), with a search cutoff date of April 23, 2024; (III) assessment of evidence quality and recommendation strength: evidence quality and recommendation opinions are graded based on the evidence category and recommendation level of the Chinese Society of Clinical Oncology (CSCO) guidelines; (IV) consensus formulation: on the March 2, 2024, through online consensus meeting, the consensus content is thoroughly discussed, and opinions from all experts are solicited. Results: The consensus meeting has resulted in 15 detailed recommendations, providing clearer guidance on the clinical application of immunotherapy in BC management. The core suggestions are as follows: for early-stage II-III TNBC and metastatic TNBC (mTNBC) in the first-line setting, programmed cell death protein 1 (PD-1) inhibitors can be considered. However, for hormone receptor-positive/human epidermal growth factor receptor 2-negative BC (HR+/HER2- BC), HER2+ BC, and mTNBC in later lines of therapy, evidence is lacking to support the use of immunotherapy. Conclusions: This consensus provides a comprehensive overview of BC immunotherapy, including immunotherapy for early-stage BC and late-stage BC, immune related adverse event (irAE) management, biomarkers of immunotherapy, and future directions. The consensus consolidates these deliberations into 15 evidence-based recommendations, serving as a practical guide for clinicians to more scientifically and systematically manage the clinical application of immunotherapy.

Marine-derived EGFR inhibitors: novel compounds targeting breast cancer growth and drug resistance.

Breast cancer (BC) continues to be a major health challenge globally, ranking as the fifth leading cause of cancer mortality among women, despite advancements in cancer detection and treatment. In this study, we identified four novel compounds from marine organisms that effectively target and inhibit the Epidermal Growth Factor Receptor (EGFR), crucial for BC cell growth and proliferation. These compounds not only induced early apoptosis through Caspase-3 activation but also showed significant inhibitory effects on EGFR mutations associated with drug resistance (T790M, L858R, and L858R/T790M), demonstrating high EGFR kinase selectivity. Cell Thermal Shift Assay (CETSA) experiments indicated that Tandyukisin stabilizes EGFR in a concentration-dependent manner. Furthermore, binding competition assays using surface plasmon resonance technology revealed that Tandyukisin and Trichoharzin bound to distinct sites on EGFR and that their combined use enhanced apoptosis in BC cells. This discovery may pave the way for developing new marine-derived EGFR inhibitors, offering a promising avenue for innovative cancer treatment strategies and addressing EGFR-mediated drug resistance.

A Nanorobotics-Based Approach of Breast Cancer in the Nanotechnology Era.

We are living in an era of advanced nanoscience and nanotechnology. Numerous nanomaterials, culminating in nanorobots, have demonstrated ingenious applications in biomedicine, including breast cancer (BC) nano-theranostics. To solve the complicated problem of BC heterogeneity, non-targeted drug distribution, invasive diagnostics or surgery, resistance to classic onco-therapies and real-time monitoring of tumors, nanorobots are designed to perform multiple tasks at a small scale, even at the organelles or molecular level. Over the last few years, most nanorobots have been bioengineered as biomimetic and biocompatible nano(bio)structures, resembling different organisms and cells, such as urchin, spider, octopus, fish, spermatozoon, flagellar bacterium or helicoidal cyanobacterium. In this review, readers will be able to deepen their knowledge of the structure, behavior and role of several types of nanorobots, among other nanomaterials, in BC theranostics. We summarized here the characteristics of many functionalized nanodevices designed to counteract the main neoplastic hallmark features of BC, from sustaining proliferation and evading anti-growth signaling and resisting programmed cell death to inducing angiogenesis, activating invasion and metastasis, preventing genomic instability, avoiding immune destruction and deregulating autophagy. Most of these nanorobots function as targeted and self-propelled smart nano-carriers or nano-drug delivery systems (nano-DDSs), enhancing the efficiency and safety of chemo-, radio- or photodynamic therapy, or the current imagistic techniques used in BC diagnosis. Most of these nanorobots have been tested in vitro, using various BC cell lines, as well as in vivo, mainly based on mice models. We are still waiting for nanorobots that are low-cost, as well as for a wider transition of these favorable effects from laboratory to clinical practice.

Biological Basis of Breast Cancer-Related Disparities in Precision Oncology Era.

Precision oncology is based on deep knowledge of the molecular profile of tumors, allowing for more accurate and personalized therapy for specific groups of patients who are different in disease susceptibility as well as treatment response. Thus, onco-breastomics is able to discover novel biomarkers that have been found to have racial and ethnic differences, among other types of disparities such as chronological or biological age-, sex/gender- or environmental-related ones. Usually, evidence suggests that breast cancer (BC) disparities are due to ethnicity, aging rate, socioeconomic position, environmental or chemical exposures, psycho-social stressors, comorbidities, Western lifestyle, poverty and rurality, or organizational and health care system factors or access. The aim of this review was to deepen the understanding of BC-related disparities, mainly from a biomedical perspective, which includes genomic-based differences, disparities in breast tumor biology and developmental biology, differences in breast tumors' immune and metabolic landscapes, ecological factors involved in these disparities as well as microbiomics- and metagenomics-based disparities in BC. We can conclude that onco-breastomics, in principle, based on genomics, proteomics, epigenomics, hormonomics, metabolomics and exposomics data, is able to characterize the multiple biological processes and molecular pathways involved in BC disparities, clarifying the differences in incidence, mortality and treatment response for different groups of BC patients.

A novel immune-related long noncoding RNA (lncRNA) pair model to predict the prognosis of triple-negative breast cancer.

Background: Breast cancer (BC) is the most prevalent cancer type and is the principal cause of cancer-related death in women. Anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) immunotherapy has shown promising effects in metastatic triple-negative breast cancer (TNBC), but the potential factors affecting its efficacy have not been elucidated. Immune-related long noncoding RNAs (irlncRNAs) have been reported to be involved in immune escape to influence the carcinogenic process through the PD-1/PD-L1 signaling pathway. Therefore, exploring the potential regulatory mechanism of irlncRNAs in PD-1/PD-L1 immunotherapy in TNBC is of great importance. Methods: We retrieved transcriptome profiling data from The Cancer Genome Atlas (TCGA) and identified differentially expressed irlncRNA (DEirlncRNA) pairs. Least absolute shrinkage and selection operator (LASSO) regression analysis was performed to construct a risk assessment model. Results: Receiver operating characteristic (ROC) curve analysis indicated that the risk model may serve as a potential prediction tool in TNBC patients. Clinical stage and risk score were proved to be independent prognostic predictors by univariate and multivariate Cox regression analyses. Subsequently, we investigated the correlation between the risk model and tumor-infiltrating immune cells and immune checkpoints. Finally, we identified USP30-AS1 through the StarBase and Multi Experiment Matrix (MEM) databases, predicted the potential target genes of USP30-AS1, and then discovered that these target genes were closely associated with immune responses. Conclusions: Our study constructed a risk assessment model by irlncRNA pairs regardless of expression levels, which contributed to predicting the efficacy of immunotherapy in TNBC. Furthermore, the lncRNA USP30-AS1 in the model was positively correlated with the expression of PD-L1 and provided a potential therapeutic target for TNBC.

A novel PD-1/PD-L1 pathway-related seven-gene signature for the development and validation of the prognosis prediction model for breast cancer.

Background: Breast cancer (BC/BRCA) is the most common carcinoma in women. The average 5-year survival rate of BC patients with stage IV disease is 26%. A considerable proportion of patients still do not receive effective therapy. It is an unmet need to identify novel biomarkers for BC patients. Herein, we evaluated whether the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) status is associated with the clinical outcomes of BC, based on data from The Cancer Genome Atlas (TCGA). Methods: Clinical and transcriptome data of BC patients were obtained from TCGA dataset, and prognostic genes in BC patients were identified, as well as the PD-1/PD-L1 pathway mainly associating with the BC patients. Following the execution of the consensus clustering algorithm, BC patients were segregated into two clusters, and subsequent investigation of the potential mechanisms between them was carried out. A comparison of ferroptosis and N6-methyladenosine (m6A) was conducted between the two groups with the greatest difference in prognosis. Based on least absolute shrinkage and selection operator (LASSO) analysis, a signature associated with the PD-1/PD-L1 pathway was developed, and the prognosis outcome and the predictive accuracy of the signature model were further assessed. Results: Prognostic genes in BC patients were studied using TCGA data and it was found that the PD-1/PD-L1 pathway was most associated with the BC patients. Then, a low-risk (C1) group and a high-risk (C2) group of BC patients were constructed based on a PD-1/PD-L1 pathway-related signature. The functional analyses suggested that the underlying mechanisms between these groups were mainly associated with immune-related pathways. We found that ferroptosis and m6A were significantly different between the two groups. A PD-1/PD-L1 pathway-related gene signature was further developed to predict survival of BC patients, including 7 genes [mitogen-activated protein kinase kinase 6 (MAP2K6), NF-kappa-B inhibitor alpha (NFKBIA), NFKB Inhibitor Epsilon (NFKBIE), Interferon gamma (IFNG), Toll/interleukin-1 receptor domain-containing adapter protein (TIRAP), IkappaB kinase (CHUK), and Casein kinase 2 alpha 3 gene (CSNK2A3)]. The receiver operating characteristic (ROC) curves were analyzed to further assess the prognostic values of these 7 genes. The 1-, 3-, and 5-year values of the areas under the curve (AUCs) for overall survival were 0.651, 0.658, and 0.653 in this seven gene signature model, respectively. Conclusions: PD-1/PD-L1 pathway-related subtypes of BC were identified, which were closely associated with the immune microenvironment, the ferroptosis status, and m6A in BC patients. The gene signature involved in the PD-1/PD-L1 pathway might help to make a distinction and predict prognosis in BC patients.

An integrated approach to understand the regulatory role of miR-27 family in breast cancer metastasis.

One of the prime reasons of increasing breast cancer mortality is metastasizing cancer cells. Owing to the side effects of clinically available drugs to treat breast cancer metastasis, it is of utmost importance to understand the underlying biogenesis of breast cancer tumorigenesis. In-silico identification of potential RNAs might help in utilizing the miR-27 family as a therapeutic target in breast cancer. The experimentally verified common interacting mRNAs for miR27 family are retrieved from three publicly available databases- TargetScan, miRDB and miRTarBase. Finally on comparing the common genes with HCMDB and GEPIA data, four breast cancer-associated differentially expressed metastatic mRNAs (GATA3, ENAH, ITGA2 and SEMA4D) are obtained. Corresponding to the miR27 family and associated mRNAs, interacting drugs are retrieved from Sm2mir and CTDbase, respectively. The interaction network-based approach was utilized to obtain the hub RNAs and triad modules by employing the 'Cytohubba' and 'MClique' plugins, respectively in Cytoscape. Further, sample-, subclass- and promoter methylation-based expression analyses reveals GATA3 and ENAH to be the most significant mRNAs in breast cancer metastasis having >10% genetic alteration in both METABRIC Vs TCGA datasets as per their oncoprint analysis via cBioPortal. Additionally, survival analysis in Oncolnc reveals SEMA4D as survival biomarker. Interactions among the miR27 family, their target mRNAs and drugs interacting with miRNAs and mRNAs can be extensively explored in both in-vivo and in-vitro setups to assess their therapeutic potential in the diminution of breast cancer.

A WeChat-based nursing intervention program improves the postoperative rehabilitation of breast cancer patients: results from a randomized controlled trial.

Background: In postoperative setting, breast cancer (BC) patients can experience adverse effects, including fatigue, sleep disorders, and pain, which substantially affect their health-related quality of life (HRQoL). This study sought to assess the effectiveness of a WeChat-based multimodal nursing program (WCBMNP) that was specifically designed for the rehabilitation of women following BC surgery. Methods: BC patients were randomly, single-blinded allocated to either the intervention (n=62) or control (n=63) cohorts. Over a period of 6 months (24 weeks), the intervention cohort received a WCBMNP in addition to routine nursing care, while the control cohort received routine nursing care only. To evaluate patients' fear of cancer recurrence (FCR), their overall fear score was assessed using the Japanese version of the Concerns About Recurrence Scale (CARS-J) for primary outcome. The initial outcome (HRQoL) and secondary results, such as fatigue, sleep, and pain, were examined using the Functional Assessment of Cancer Therapy-Breast (FACT-B, version 4.0) and Nursing Rating Scale (NRS), respectively. Results: Two hundred and ten participants, 85 participants were excluded. Compared to the controls (n=63), the intervention cohort (n=62) showed statistically significant improvements in their CARS-J scores. The intervention cohort aggregate scores on the FACT-B improved significantly but were affected by the compounding influences of cohort dynamics, temporal progression, and their interaction. Similar improvements were observed in the social/family and functional well-being domains. Emotional well-being was improved based on the effects of time and group-time interaction. In the intervention cohort, the "BC-specific subscale for additional concerns" was affected by group and time, whereas physical well-being was only affected by time. Conversely, there were no statistically significant changes in the variables of fatigue, sleep, and pain. Conclusions: The WCBMNP reduced FCR and significantly increased the HRQoL of female patients with BC postoperatively. The WCBMNP could be implemented as a postoperative rehabilitation intervention in this patient population to improve outcomes. Trial Registration: Chinese Clinical Trial Registry (ChiCTR2400081557).

Tumor-derived mesenchymal progenitor cell-related genes in the regulation of breast cancer proliferation.

Background: Breast cancer (BC) is one of the most common malignancies worldwide, and its development is affected in various ways by the tumor microenvironment (TME). Tumor-derived mesenchymal progenitor cells (MPCs), as the most important components of the TME, participate in the proliferation and metastasis of BC in several ways. In this study, we aimed to characterize the genes associated with tumor-derived MPCs and determine their effects on BC cells. Methods: Tumor-derived MPCs and normal breast tissue-derived mesenchymal stem cells (MSCs) were isolated from tissues specimens of patients with BC. We conducted culture and passage, phenotype identification, proliferation and migration detection, inflammatory factor release detection, and other experiments on isolated MPCs from tumors and MSCs from normal breast tissues. Three paired tumor-derived MPCs and normal breast tissue-derived MSCs were then subjected to transcriptome analysis to determine the expression profiles of the relevant genes, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to further confirm gene expression. Subsequently, the overexpression plasmids were transfected into tumor-derived MPCs, and the expression of various inflammatory factors of tumor-derived MPCs and their proliferation were characterized with a cell viability test reagent (Cell Counting Kit 8). Subsequently, the transfected tumor-derived MPCs were cocultured with BC cells using a conditioned medium coculture method to clarify the role of tumor-derived MSCs in BC. Results: Tumor-derived MPCs expressed stem cell characteristics including CD105, CD90, and CD73 and exhibited adipogenic and osteogenic differentiation in vitro. The proliferation of tumor-derived MPCs was significantly lower than that of normal breast tissue-derived MSCs, and the invasive metastatic ability was comparable; however, MPCs were found to release inflammatory factors such as interleukin 6 (IL-6) and transforming growth factor ß (TGF-ß). Transcriptome analysis showed that stomatin (STOM), collagen and calcium binding EGF domains 1 (CCBE1), and laminin subunit alpha 5 (LAMA5) were significantly upregulated in tumor-derived MPCs. Among them, STOM was highly expressed in tumor-derived MPCs, which mediated the slow proliferation of MPCs and promoted the proliferation of BC cells. Conclusions: STOM, CCBE1, and LAMA5 were highly expressed in tumor-derived MPCs, with STOM being found to retard the proliferation of MPCs but promote the proliferation of BC cells. There findings present new possibilities in targeted microenvironmental therapy for BC.

Short-term efficacy and safety of neoadjuvant pyrotinib plus taxanes for early HER2-positive breast cancer: a single-arm exploratory phase II trial.

Background: The effectiveness and safety of pyrotinib have been substantiated in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC). However, the role of pyrotinib as a single HER2 blockade in neoadjuvant setting among BC patients has not been studied. The objective of this study was to evaluate the efficacy and tolerability of pyrotinib plus taxanes as a novel neoadjuvant regimen in patients with HER2-positive early or locally advanced BC. Methods: In this single-arm exploratory phase II trial, patients with treatment-naïve HER2-positive BC (stage IIA-IIIC) received pyrotinib 400 mg once daily and taxanes [docetaxel 75 mg/m2 or nanoparticle albumin-bound (nab)-paclitaxel 260 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly] for a total of four 21-day cycles before surgery. Efficacy assessment was based on pathological and clinical measurements. The primary endpoint of this study was the total pathological complete response (tpCR) rate. The secondary endpoints included breast pCR (bpCR) rate, investigator-assessed objective response rate (ORR) and adverse events (AEs) profiles. Results: From 1 September 2021 to 30 December 2022, a total of 31 patients were enrolled. One patient was withdrawn due to unbearable skin rash after the second cycle of neoadjuvant therapy. The majority of the intention-to-treat (ITT) population was premenopausal (54.8%), had large tumors (90.3%) and metastatic nodes (58.1%) at diagnosis and hormone-receptor positive tumors (64.5%). Most participants used nab-paclitaxel (74.2%) and received mastectomy (67.7%) after neoadjuvant treatment. The tpCR and bpCR rates were 48.4% [95% confidence interval (CI): 30.8-66%] and 51.6% (95% CI: 34-69.2%), respectively. Grade ≥3 treatment-related AEs were observed in 16.1% (5/31) of the ITT population, including diarrhea (n=2, 6.5%), hand and foot numbness (n=1, 3.2%), loss of appetite (n=1, 3.2%), and skin rash (n=1, 3.2%). AE related dose reduction or pyrotinib interruption was not required. Conclusions: In female patients with HER2-positive non-metastatic BC, neoadjuvant pyrotinib monotherapy plus taxanes appears to show promising clinical benefit and controllable AEs [Chinese Clinical Trial Registry (ChiCTR2100050870)]. The long-term efficacy and safety of this regime warrant further verification.

Systematic analysis of PANoptosis-related genes identifies XIAP as a functional oncogene in breast cancer.

BACKGROUND: Breast cancer (BC) is the most prevalent malignant disease affecting women globally. PANoptosis, a novel form of cell death combining features of pyroptosis, apoptosis, and necroptosis, has recently gained attention. However, its precise function in BC and the predictive values of PANoptosis-related genes remain unclear. METHODS: We used the expression data and clinical information of BC tissues or normal breast tissues from public databases, and then successfully developed and verified a BC PANoptosis-related risk model through a combination of univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, and Kaplan-Meier (KM) analysis. A nomogram was constructed to estimate survival probability, and its accuracy was assessed using calibration curves. RESULTS: Among 37 PANoptosis-related genes, we identified 4 differentially expressed genes related to overall survival (OS). Next, a risk model incorporating these four PANoptosis-related genes was established. Patients were stratified into low/high-risk groups based on the median risk score, with the low-risk group showing better prognoses and higher levels of immune infiltration. Utilizing the risk score and clinical features, we developed a nomogram to predict 1-, 3- and 5-year survival probability. X-linked inhibitor of apoptosis protein (XIAP) emerged as a potentially risky factor with the highest hazard ratio. In vitro experiments demonstrated that XIAP inhibition enhances the antitumor effect of doxorubicin through the PANoptosis pathway. CONCLUSION: PANoptosis holds an important role in BC prognosis and treatment.