Explore the vast range of titles available.

Single‐cell RNA sequencing (scRNA‐seq) is a novel technology that allows transcriptomic analyses of individual cells. During the past decade, scRNA‐seq sensitivity, accuracy, and efficiency have improved due to innovations including more sensitive, automated, and cost‐effective single‐cell isolation methods with higher throughput as well as ongoing technological development of scRNA‐seq protocols. Among the variety of current approaches with distinct features, researchers can choose the most suitable method to carry out their research. By profiling single cells in a complex population mix, scRNA‐seq presents great advantages over traditional sequencing methods in dissecting heterogeneity in cell populations hidden in bulk analysis and exploring rare cell types associated with tumorigenesis and metastasis. scRNA‐seq studies in recent years in the field of breast cancer research have clustered breast cancer cell populations with different molecular subtypes to identify distinct populations that may correlate with poor prognosis and drug resistance. The technology has also been used to explain tumor microenvironment heterogeneity by identifying distinct immune cell subsets that may be associated with immunosurveillance and are potential immunotherapy targets. Moreover, scRNA‐seq has diverse applications in breast cancer research besides exploring heterogeneity, including the analysis of cell‐cell communications, regulatory single‐cell states, immune cell distributions, and more. scRNA‐seq is also a promising tool that can facilitate individualized therapy due to its ability to define cell subsets with potential treatment targets. Although scRNA‐seq studies of therapeutic selection in breast cancer are currently limited, the application of this technology in this field is prospective. Joint efforts and original ideas are needed to better implement scRNA‐seq technologies in breast cancer research to pave the way for individualized treatment management. This review provides a brief introduction on the currently available scRNA‐seq approaches along with their corresponding strengths and weaknesses and may act as a reference for the selection of suitable methods for research. We also discuss the current applications of scRNA‐seq in breast cancer research for tumor heterogeneity analysis, individualized therapy, and the other research directions mentioned above by reviewing corresponding published studies. Finally, we discuss the limitations of current scRNA‐seq technologies and technical problems that remain to be overcome.

Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy, chemotherapy, targeted drug therapy and immunotherapy. In recent years, immunotherapy has potentiated the survival of certain breast cancer patients; however, primary resistance or acquired resistance attenuate the therapeutic outcomes. Histone acetyltransferases induce histone acetylation on lysine residues, which can be reversed by histone deacetylases (HDACs). Dysregulation of HDACs via mutation and abnormal expression contributes to tumorigenesis and tumor progression. Numerous HDAC inhibitors have been developed and exhibited the potent anti-tumor activity in a variety of cancers, including breast cancer. HDAC inhibitors ameliorated immunotherapeutic efficacy in cancer patients. In this review, we discuss the anti-tumor activity of HDAC inhibitors in breast cancer, including dacinostat, belinostat, abexinostat, mocetinotat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. Moreover, we uncover the mechanisms of HDAC inhibitors in improving immunotherapy in breast cancer. Furthermore, we highlight that HDAC inhibitors might be potent agents to potentiate immunotherapy in breast cancer.

The prognostic values of tumor-infiltrating lymphocytes (TILs) and TILs subsets in breast cancer (BC) are uncertain. A systematic literature search (MEDLINE, Web of Science, EMBASE, and the Cochrane Library to August 2014) was conducted for studies which met the eligibility criteria. The primary clinical outcome was defined as disease-free survival (DFS), overall survival (OS), and BC-specific survival (BCSS). Random or fixed-effects model was adopted to estimate the summary hazard ratio (HR). Twenty-five published studies comprising 22,964 patients were reviewed. Pooled analysis indicated that TILs were not prognostic markers for DFS and OS in overall population, but related to improved DFS (HR, 0.82; 95% CI, 0.76-0.88) and OS (HR, 0.79; 95% CI, 0.71-0.87) in triple negative breast cancer (TNBC) patients. For TILs subsets, CD8+ lymphocytes were associated with improved DFS (HR, 0.69; 95% CI, 0.56-0.84) and BCSS (HR, 0.78; 95% CI, 0.71-0.86) in overall population, while FOXP3+ lymphocytes were associated with reduced DFS (HR, 1.47; 95% CI, 1.01-2.05) and OS (HR, 1.50; 95% CI, 1.15-1.97). In estrogen receptor (ER) negative patients, CD8+ lymphocytes was also related to better BCSS. In addition, the high density of CD20+, CD3+ or low level of PD-1+ or γδ T lymphocytes indicated increased OS in limited studies. TILs and TILs subsets are promising prognostic biomarkers in breast cancer, especially in TNBC.

We carried out a systematic review and meta-analysis to evaluate the predictive roles of tumor infiltrating lymphocytes (TILs) in response to neoadjuvant chemotherapy (NAC) in breast cancer. A PubMed and Web of Science literature search was designed. Random or fixed effect models were adopted to estimate the summary odds ratio (OR). Heterogeneity and sensitivity analyses were performed to explore heterogeneity among studies and to assess the effects of study quality. Publication bias was evaluated using a funnel plot, Egger's test and Begg's test. We included studies where the predictive significance of TILs, and/or TILs subset on the pathologic complete response (pCR) were determined in NAC of breast cancer. A total of 13 published studies (including 3251 patients) were eligible. In pooled analysis, the detection of higher TILs numbers in pre-treatment biopsy was correlated with better pCR to NAC (OR = 3.93, 95% CI, 3.26-4.73). Moreover, TILs predicted higher pCR rates in triple negative (OR = 2.49, 95% CI: 1.61-3.83), HER2 positive (OR = 5.05, 95% CI: 2.86-8.92) breast cancer, but not in estrogen receptor (ER) positive (OR = 6.21, 95%CI: 0.86-45.15) patients. In multivariate analysis, TILs were still an independent marker for high pCR rate (OR = 1.41, 95% CI: 1.19-1.66). For TILs subset, higher levels of CD8+ and FOXP3+ T-lymphocytes in pre-treatment biopsy respectively predicted better pathological response to NAC (OR = 6.44, 95% CI: 2.52-16.46; OR = 2.94, 95% CI: 1.05-8.26). Only FOXP3+ lymphocytes in post-NAC breast tissue were a predictive marker for low pCR rate in univariate (OR = 0.41, 95% CI: 0.21-0.80) and multivariate (OR = 0.36, 95% CI: 0.13-0.95) analysis. Higher TILs levels in pre-treatment biopsy indicated higher pCR rates for NAC. TILs subset played different roles in predicting response to NAC.

Cancer is a systemic disease encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion, and metastasis. In breast cancer, CAFs not only promote tumor progression but also induce therapeutic resistance. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistance. This review summarizes the current understandings of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. In addition, the effects of other stromal components such as endothelial cells, macrophages, and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to categorize patients into a specific and confirmed subtype for personalized treatment.

Cancer-associated adipocytes (CAAs), one of the primary stromal components, exhibit intimate crosstalk and release multiple cell factors mediating local and systemic biological effects. However, the role of CAAs in the regulation of systemic immune responses and their potential value in the clinical treatment of triple-negative breast cancer (TNBC) are not well described. Transcriptome sequencing was performed on CAA and normal adipocyte (NA) tissues isolated from surgically resected samples from TNBC patients and healthy controls. Cytokines, including C-X-C motif chemokine ligand 8 (CXCL8, also known as IL-8), secreted from NAs and CAAs were compared by transcriptome sequencing and enzyme-linked immunosorbent assay (ELISA). Proliferation, migration and invasion assays were employed to analyze the role of CAAs and CAA-derived CXCL8 (macrophage inflammatory protein-2 (MIP2) as a functional surrogate in mice). TNBC syngraft models were established to evaluate the curative effect of targeting CXCL8 in combination with anti-PD-1 therapies. Real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), polymerase chain reaction (PCR) array, flow cytometry, immunohistochemistry (IHC), and immunofluorescence (IF) were applied to analyze immune cell infiltration and epithelial–mesenchymal transition (EMT) markers. Specifically, we demonstrated that CAAs and CAA-derived CXCL8 played important roles in tumor growth, EMT, metastasis and tumor immunity suppression. CAA-derived CXCL8 remodeled the tumor immune microenvironment not only by suppressing CD4 + T and CD8 + T immune cell infiltration but also by upregulating CD274 expression in TNBC. The combination of targeting the CXCL8 pathway and blocking the PD-1 pathway synergistically increased the tumor immune response and inhibited tumor progression. Thus, our results highlight the molecular mechanisms and translational significance of CAAs in tumor progression and immune ecosystem regulatory effects and provide a better understanding of the potential clinical benefit of targeting CAA-derived CXCL8 in antitumor immunity and as a new therapeutic moiety in TNBC.

Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization. Stat6 promotes M2 macrophage polarization. Here the authors characterize Trim24-CBP-Stat6 circuit regulating M2 macrophage polarization via Stat6 acetylation, and show it contributes to pro-tumorigenic macrophage activity in mice.

Background: Although there are reports of adverse events (AEs) of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, the safety of ribociclib alone has not yet been comprehensively evaluated in real-world clinical practice. Objectives: To investigate the overall real-world safety profile of ribociclib by mining data from the FDA Adverse Event Reporting System (FAERS). Design: A retrospective disproportionality analysis was conducted based on the FAERS database. Methods: We processed reports from the first quarter of 2017 to the second quarter of 2023 and applied disproportionality analysis using four different methods: reporting odds ratio, Medicines and Healthcare Products Regulatory Agency, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. Results: A total of 12,885 AE reports of ribociclib as the primary suspect were enrolled. 48.81% of AEs occur within 60 days of ribociclib administration. Blood and lymphatic system disorders and abnormalities in investigation at the system organ class level showed statistically significant signals in all four methods. Nausea (n = 1426), neutropenia (n = 940), vomiting (n = 863), white blood cell count decreased (n = 812), and alopecia (n = 536) turned out to be the five most frequent AEs at the preferred term level. Twenty-eight AEs undiscovered in the label were newly identified. Neutropenia, as a widely recognized AE, was observed to potentially result in more serious outcomes than previously anticipated (p < 0.001). Conclusion: This study utilized the FAERS database to analyze real-world AE signals associated with ribociclib following its market approval. We characterized the clinical profiles of reported AEs and found some significant signals consistent with previous clinical trials. In addition, several AEs not included in the drug label or exhibiting unexpected severity were detected. These findings provide valuable insights for clinicians and highlight directions for further causality-focused research to validate the observed results. Plain language summary An analysis of the safety of ribociclib after its marketing based on the FDA Adverse Event Reporting System Why was the study done? Ribociclib, as an anti-cancer drug mainly applied to breast cancer patients, is now widely used. However, its comprehensive safety profile remains unrevealed. The researchers aim to use the adverse event reports registered in the FDA Adverse Event Reporting System to give a general view of adverse events of ribociclib in the real-world clinical practice after its marketing. What did the researchers do? The researchers collected reports from the first quarter of 2017 to the second quarter of 2023, analyzed the data and detected the signals of adverse events associated with ribociclib at different levels utilizing four different statistical methods. How is the study designed? This study is a disproportionality analysis, which analyzed the past data from the FAERS database. What did the researchers find? The researchers analyzed 12,885 reports in which ribociclib was suspected as the primary cause of the adverse event. Here are the main findings: - Almost half of the adverse events occur in the first 60 days of ribociclib using. - “Blood and lymphatic system disorders” and abnormalities in “Investigation” showed significant signals in all four methods used. Nausea, neutropenia, vomiting, white blood cell count decreased, and alopecia were the five most common adverse events with ribociclib. These were consistent with previous clinical trials. - 28 adverse events undiscovered in the drug label were identified. - Among the widely recognized adverse events, neutropenia could result in more serious outcomes than common knowledge. What do the findings mean? This study could serve as a warning to clinicians and provide a direction for further studies. Follow-up researches based on long-term data or further prospective studies are necessary to validate the results of our study and to reveal the causality.

Background: Multidisciplinary treatment (MDT) and adjuvant therapy are associated with improved survival rates in breast cancer. However, nonadherence to MDT decisions is common in patients. We developed a smartphone-based app that can facilitate the full-course management of patients after surgery. Objective: This study aims to investigate the influence factors of treatment nonadherence and to determine whether this smartphone-based app can improve the compliance rate with MDTs. Methods: Patients who had received a diagnosis of invasive breast cancer and had undergone MDT between March 2013 and May 2019 were included. Patients were classified into 3 groups: Pre-App cohort (November 2017, before the launch of the app); App nonused, cohort (after November 2017 but not using the app); and App used cohort (after November 2017 and using the app). Univariate and multivariate analyses were performed to identify the factors related to MDT adherence. Compliance with specific adjuvant treatments, including chemotherapy, radiotherapy, endocrine therapy, and targeted therapy, was also evaluated. Results: A total of 4475 patients were included, with Pre-App, App nonused, and App used cohorts comprising 2966 (66.28%), 861 (19.24%), and 648 (14.48%) patients, respectively. Overall, 15.53% (695/4475) patients did not receive MDT recommendations; the noncompliance rate ranged from 27.4% (75/273) in 2013 to 8.8% (44/500) in 2019. Multivariate analysis demonstrated that app use was independently associated with adherence to adjuvant treatment. Compared with the patients in the Pre-App cohort, patients in the App used cohort were less likely to deviate from MDT recommendations (odds ratio [OR] 0.61, 95% CI 0.43-0.87; P=.007); no significant difference was found in the App nonused cohort (P=.77). Moreover, app use decreased the noncompliance rate for adjuvant chemotherapy (OR 0.41, 95% CI 0.27-0.65; P<.001) and radiotherapy (OR 0.49, 95% CI 0.25-0.96; P=.04), but not for anti-HER2 therapy (P=.76) or endocrine therapy (P=.39). Conclusions: This smartphone-based app can increase MDT adherence in patients undergoing adjuvant therapy; this was more obvious for adjuvant chemotherapy and radiotherapy.

Background: The association between dyslipidaemia and breast cancer remains controversial, especially regarding the dynamic changes in lipid levels. Objectives: This study aimed to elucidate the role of serum lipid levels and the changes in disease outcomes in patients with breast cancer. Methods: The lipid profiles of patients with breast cancer who underwent surgery between 2013 and 2017 were retrospectively reviewed. The lipid profiles comprised triglyceride (TG), total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein. Serum lipid levels were categorized into three groups based on the tertiles. The Wilcoxon test was used to compare changes in serum lipid levels during follow-up. Hazard ratios (HRs) for survival outcomes were estimated using a multivariate Cox regression analysis. Results: A total of 3499 women diagnosed with nonmetastatic invasive breast cancer were included in this study, with a median follow-up of 60.4 months. We confirmed that each 1-tertile increased TG at baseline [HR = 1.19, 95% confidence interval (CI) 1.02–1.39] and 1-year follow-up (HR = 1.46, 95% CI 1.07–1.98) led to worse relapse-free survival (RFS). A lower risk of disease relapse was observed with each 1-tertile upregulation in HDL at 1-year follow-up (HR = 0.72, 95% CI 0.56–0.92). Receiving systemic therapies tends to induce an elevation in plasma lipid levels 1 year after surgery, especially in terms of TG. Regarding the prognostic value of dynamic changes in lipid levels, patients with sustained high levels of TG had poorer RFS (HR = 1.90, 95% CI 1.16–3.11), whereas maintaining high levels of HDL led to better survival (HR = 0.60, 95% CI 0.37–0.97). Conclusion: High TG at baseline and during follow-up was associated with worse disease outcome in early breast cancer patients. Systemic treatment would lead to an elevation of serum lipid levels. Patients with sustained high HDL level at 1-year follow-up after surgery had a superior prognosis, warranting further clinical evaluation.