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Compared with other types of breast cancer, triple-negative breast cancer (TNBC) has the characteristics of rapid progression, a lack of specific molecular targets for treatment and a poor prognosis. However, based on previously published studies, TGF-β1 and survivin are potentially meaningful for the prognosis of patients with TNBC. The present study was therefore designed to measure and compare the expression of transforming growth factor-β1 (TGF-β1) and survivin in tissue samples of TNBC and non-TNBC patients in order to evaluate their ability as prognostic indicators. In total, 90 TNBC and 52 non-TNBC tissue specimens were selected, following which immunohistochemistry was used to detect the expression of TGF-β1 and survivin in the cancer tissues. Subsequently, the potential association between the expression levels of these two proteins and the clinicopathological variables was analyzed. The expression levels of TGF-β1 and survivin in TNBC tissues were found to be significantly higher compared with those in the non-TNBC tissues. In addition, the results of the present study demonstrated that TGF-β1 expression was positively associated with survivin expression in the TNBC samples, but no significant correlation was found between TGF-β1 and survivin expression in the non-TNBC samples. Kaplan-Meier (K-M) analysis was performed to assess the levels of TGF-β1 and survivin in regard to patient survival, and univariate and multivariate Cox analyses of TGF-β1 and survivin protein expression were performed to analyze the overall survival (OS) and progression-free survival (PFS) rates of patients with TNBC and non-TNBC. Although multivariate Cox analysis demonstrated that neither TGF-β1 or survivin were independent prognostic predictors of TNBC or non-TNBC, results of the K-M curve revealed that patients with TNBC with TGF-β1- and survivin-positive breast cancer exhibited shorter OS and PFS times. Multivariate Cox analysis demonstrated that in patients with TNBC, the combined expression of TGF-β1 and survivin may yield additional prognostic information, compared with patients with non-TNBC.

Breast cancer is a heterogeneous disease and is one of the most prevalent cancers in women. Triple‐negative breast cancer (TNBC) is a relatively aggressive subtype of breast cancer, which is difficult to treat. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein that is overexpressed in various types of cancers, including breast cancer, especially TNBC. In this study, bioinformatic analyses revealed enhanced fibroblast growth factor receptor 1 (FGFR1) signaling in patients with invasive breast cancer, and the GPNMBhigh/FGFR1high group exhibited a lower probability of relapse‐free survival (RFS) than the GPNMBlow/FGFR1low group. Additionally, we observed that GPNMB and FGFR1 were essential for sphere formation, cellular migration, and epithelial‐mesenchymal transition (EMT)‐like changes in TNBC cells. To explore the mutual interaction between these two molecules, we conducted in silico protein–protein docking studies and molecular dynamics simulations. The results revealed that GPNMB isoform b exhibits high binding affinity for FGFR1 isoform c (FGFR1c), which correlates with cancer aggressiveness. We also confirmed the interaction between GPNMB and FGFR1 in TNBC cells. Furthermore, our study demonstrated that GPNMB is essential for AKT phosphorylation at T308 following FGF2 stimulation, resulting in high affinity for FGFR1c. Inhibition of AKT phosphorylation substantially reduces the tumorigenic potential of TNBC cells. In the present study, we showed that the combination of glycoprotein nonmetastatic melanoma protein B (GPNMB) and fibroblast growth factor receptor 1 (FGFR1) would be a novel poor prognostic indicator in patients with triple‐negative breast cancer (TNBC.) Furthermore, we found GPNMB as a novel binding partner of FGFR1, and they are important for the tumorigenic ability of TNBC cells through the regulation of AKT phosphorylation. Therefore, this association could be the potential therapeutic target to control TNBC.

Abnormal activation of the nuclear factor‐kappa B (NF‐κB) signaling pathway is closely implicated in triple‐negative breast cancer growth, metastasis, and tumor immune escape. In this study, the anti‐cancer effects of icariin, a natural flavonol glycoside, toward breast cancer cells and the underlying mechanisms were investigated. This investigation showed that icariin selectively inhibited proliferation and triggered apoptosis in breast cancer cells in a concentration‐ and time‐dependent manner, but exhibited little cytotoxicity in normal breast cells. Moreover, icariin induced cell apoptosis via a mitochondria‐mediated pathway, as indicated by the upregulated ratio of Bax/Bcl‐2 and reactive oxygen species induction. Importantly, icariin impaired the activation of the NF‐κB/EMT pathway, as evidenced by upregulation of SIRT6, resulting in inhibition of migration and invasion of breast cancer cells. Additionally, oss‐128167, an inhibitor of SIRT6, dramatically attenuated anti‐migration and anti‐invasion effects of icariin. Transcriptomic analysis verified that impairment of NF‐κB led to the selective function of icariin in breast cancer cells. Notably, icariin exhibited a significant tumor growth inhibition and anti‐pulmonary metastasis effect in a tumor mouse model of MDA‐MB‐231 and 4T1 cells by regulating the tumor immunosuppressive microenvironment. Together, these results showed that icariin could effectively trigger apoptosis and inhibit the migration of breast cancer cells via the SIRT6/NF‐κB signaling pathway, suggesting that icariin might serve as a potential candidate drug for the treatment of breast cancer. Icariin selectively induces redox‐dependent apoptosis and inhibits migration and invasion in breast cancer cells by impairing the activation of the NF‐κB signaling pathway. Icariin upregulated expression of SIRT6 to impair the NF‐κB/EMT pathway. Icariin exhibited a significant tumor growth inhibition and anti‐pulmonary metastasis effect in vivo by regulating the tumor immunosuppressive microenvironment.

There are significant differences in the biological behavior between triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC). In the present study, we identify key differential genes and clinical outcomes between TNBC and non-TNBC. Transcriptomic analyses used GEO datasets (GSE76275), gene ontology, KEGG pathway analysis and cBioPortal. Quantitative RT-PCR analysis (qRT-PCR) was used to validate the differentially expressed genes. We used the KM Plotter Online Tool and 240 patients with TNBC tissue microarray to assay the prognostic value of . The upregulated differentially expressed genes were enriched in transcription factor activity, sequence-specific DNA binding and nucleic acid binding transcription factor activity. Only 16 genes were upregulated when further screened for fold change >4-fold change. and exhibited high frequencies of change of greater than 10% ( was close to 20%). qRT-PCR results indicated that and mRNA levels were significantly upregulated in TNBC samples. In KM Plotter Online Tool, high was associated with worse outcome. In our tissue microarray (including 240 TNBC tissues), IHC analysis revealed that 29.7% (55/240) of the tumor samples exhibited high expression and 70.3% (185/240) of the tumor samples exhibited low expression levels. Meanwhile, high group has a bad prognosis. The status of transcriptional activation is an important difference between TNBC and non-TNBC. is a key differential gene associated with poor outcome in TNBC. Epigenetic therapy and agents targeting cancer/testis antigens might potentially help to customize therapies of TNBC.

Background Several accomplishments have been achieved in triple-negative breast cancer (TNBC) research over the last year. The phase III IMpassion130 trial comparing chemotherapy plus atezolizumab versus chemotherapy plus placebo brought breast cancer into the immunotherapy era. Nevertheless, despite encouraging results being obtained in this trial, many open questions remain. Main body A positive overall survival outcome was achieved only in PD-L1 + TNBC patients, suggesting a need to enrich the patient population more likely to benefit from an immunotherapeutic approach. Moreover, it remains unknown whether single-agent immunotherapy might be a good option for some patients. In this context, the discovery and implementation of novel and appropriate biomarkers are required. Focusing on the early onset of TNBC, neoadjuvant trials could represent excellent in vivo platforms to test immunotherapy agents and their potential combinations, allowing the performance of translational studies for biomarker implementation and improved patient selection. Conclusion The aim of our review is to present recent advances in TNBC treatment and to discuss open issues in order to better define potential future directions for immunotherapy in TNBC.

Breast cancer is one of the leading causes of cancer-related morbidity and mortality in women worldwide. Early diagnosis and effective treatment of all types of cancers are crucial for a positive prognosis. Patients with small tumor sizes at the time of their diagnosis have a significantly higher survival rate and a significantly reduced probability of the cancer being fatal. Therefore, many novel technologies are being developed for early detection of primary tumors, as well as distant metastases and recurrent disease, for effective breast cancer management. Theranostics has emerged as a new paradigm for the simultaneous diagnosis, imaging, and treatment of cancers. It has the potential to provide timely and improved patient care via personalized therapy. In nanotheranostics, cell-specific targeting moieties, imaging agents, and therapeutic agents can be embedded within a single formulation for effective treatment. In this review, we will highlight the different diagnosis techniques and treatment strategies for breast cancer management and explore recent advances in breast cancer theranostics. Our main focus will be to summarize recent trends and technologies in breast cancer diagnosis and treatment as reported in recent research papers and patents and discuss future perspectives for effective breast cancer therapy.

Objectives Long non‐coding RNAs (lncRNAs) have been demonstrated as crucial regulators in cancer, but whether they are involved in the immune response of cancer cells remains largely undiscovered. GATA3‐AS1 is a novel lncRNA that was upregulated in breast cancer (BC) according to online databases. However, its role in triple‐negative breast cancer (TNBC) was elusive. Methods GATA3‐AS1 expression in BC tissues and adjacent normal tissues was obtained from online databases. Loss‐of‐function assays were designed and conducted to verify the functional role of GATA3‐AS1 in TNBC cells. Bioinformatic analysis and mechanism experiments were applied to explore the downstream molecular mechanism of GATA3‐AS1. Similarly, the upstream mechanism which led to the upregulation of GATA3‐AS1 in TNBC cells was also investigated. Results GATA3‐AS1 was markedly overexpressed in TNBC tissues and cells. Knockdown of GATA3‐AS1 suppressed TNBC cell growth and enhanced the resistance of TNBC cells to immune response. GATA3‐AS1 induced the deubiquitination of PD‐L1 through miR‐676‐3p/COPS5 axis. GATA3‐AS1 destabilized GATA3 protein by promoting GATA3 ubiquitination. Conclusion GATA3‐AS1 contributed to TNBC progression and immune evasion through stabilizing PD‐L1 protein and degrading GATA3 protein, offering a new target for the treatment of TNBC.

Exosomal lncRNAs secreted by cancer cells can serve as potential biomarkers in the diagnosis and prognosis of various tumours. Here, we are committed to explore the diagnostic and prognostic value of serum exosomal XIST secreted by tumour cells to predict recurrence in patients with triple‐negative breast cancer (TNBC). Significant increments in XIST and exo‐XIST from tumour tissues and blood serum were found in reoccurring TNBC patients by comparison with non‐recurrences. Levels of serum exo‐XIST were only significantly increased in TNBC recurrence and no association with other clinicopathological parameters. Additionally, serum exo‐XIST levels could be served as an assessment of change in the load of triple‐negative breast cancer. Expressions of exo‐XIST were markedly decreased after resection of the primary breast tumours and obviously elevated at the time of recurrence. Finally, an obvious association was identified between serum exo‐XIST levels and a poorer overall survival (OS) in TNBC patients. Levels of serum exo‐XIST may serve as a diagnostic and prognostic biomarker to predict the recurrent TNBC‐loading status.

Exosomes (Exo) hold great promise as endogenous nanocarriers that can deliver biological information between cells. However, Exo are limited in terms of their abilities to target specific recipient cell types. We developed a strategy to isolate Exo exhibiting increased binding to integrin α v β 3 . Binding occurred through a modified version of a disintegrin and metalloproteinase 15 (A15) expressed on exosomal membranes (A15-Exo), which facilitated co-delivery of therapeutic quantities of doxorubicin (Dox) and cholesterol-modified miRNA 159 (Cho-miR159) to triple-negative breast cancer (TNBC) cells, both in vitro and in vivo. The targeted A15-Exo were derived from continuous protein kinase C activation in monocyte-derived macrophages. These cell-derived Exo displayed targeting properties and had a 2.97-fold higher production yield. In vitro, A15-Exo co-loaded with Dox and Cho-miR159 induced synergistic therapeutic effects in MDA-MB-231 cells. In vivo, miR159 and Dox delivery in a vesicular system effectively silenced the TCF-7 gene and exhibited improved anticancer effects, without adverse effects. Therefore, our data demonstrate the synergistic efficacy of co-delivering miR159 and Dox by targeted Exo for TNBC therapy.

The telomeric repeat‐binding factor 2 (TRF2) is a telomere‐capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti‐cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA‐based approach to reduce TRF2 expression. By performing a high‐throughput luciferase screening of 54 candidate miRNAs, we identified miR‐182‐3p as a specific and efficient post‐transcriptional regulator of TRF2. Ectopic expression of miR‐182‐3p drastically reduced TRF2 protein levels in a panel of telomerase‐ or alternative lengthening of telomeres (ALT)‐positive cancer cell lines. Moreover, miR‐182‐3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR‐182‐3p impaired tumor growth in triple‐negative breast cancer (TNBC) models, including patient‐derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs‐miR‐182‐3p were able to cross the blood–brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions. Synopsis A miRNA‐based strategy to inhibit the telomeric protein TRF2 was developed, which led to efficient decrease of triple negative breast cancer growth. miR‐182‐3p was identified as an efficient regulator of TRF2 expression in human cancer through high‐throughput miRNA luciferase screening. TRF2 inhibition by miR‐182‐3p induced DNA damage at telomeric and pericentromeric sites and consequent genomic instability. miR‐182‐3p limited the growth of Triple Negative Breast Cancer (TNBC) models by activating apoptosis. Lipid nanoparticles (LNPs) containing miR‐182‐3p reduced tumor volume in vivo in various TNBC models, including Olaparib‐resistant patient‐derived tumor xenografts. LNPs‐miR‐182‐3p crossed the blood brain barrier, showing therapeutic potential against brain metastasis. Graphical Abstract A miRNA‐based strategy to inhibit the telomeric protein TRF2 was developed, which led to efficient decrease of triple negative breast cancer growth.