TNBC Patients Research Articles

Identification of an immune cell infiltration-related gene signature for prognosis prediction in triple-negative breast cancer.

Triple-negative breast cancer TNBC with higher immunogenicity and tumor-infiltrating lymphocyte (TIL) enrichment can benefit from immunotherapy relative to other breast cancer subtypes. Our work was designed to identify the TIL-related hub genes in TNBC and construct a prognostic signature for TNBC. TNBC gene expression files were obtained from the TCGA database. CIBERSORT algorithm and random forest risk model were used for immune infiltration group division. The TIL-related differentially expressed genes (DEGs) were then selected and subject to GO, KEGG analyses and GSEA. Next, Lasso cox regression analyses were adopted for constructing a prognostic risk model, followed by evaluation using time-dependent ROC curves. The copy number variation between the two risk groups was also analyzed, and major genomic mutation types were identified. Additionally, the nomogram was constructed with calibration curve for clinical prognosis analysis. Our results showed that totally 113 TNBC samples were allocated into the high or low-immune risk groups. We identified 243 DEGs between groups, namely TIL-related DEGs, with 128 upregulated and 115 downregulated genes. Among the TIL-related DEGs, 6 hub genes (SLITRK3, PCDHGB3, NELL2, SRRM4, ASIC2 and B4GALNT2) were screened out and constructed a prognostic risk signature, which had good performance for long-term prognosis prediction. Analysis of genomic mutation showed that the TP53, PIK3CA, TTH, etc. showed high mutation frequency in the two prognostic risk groups. Moreover, the higher risk score of the prognostic risk model predicted poor overall survival in TNBC patients, and nomogram and calibration curve confirmed the potent prediction ability of this model. To sum up, six TIL-related biomarkers (SLITRK3, PCDHGB3, NELL2, SRRM4, ASIC2 and B4GALNT2) were identified and used for the construction of the prognostic risk model, which might provide novel insight for the clinical decisions.

Multiomics and single‐cell sequencings reveal the specific biological characteristics of low Ki‐67 triple‐negative breast cancer

AbstractBackgroundTriple‐negative breast cancer (TNBC) displays high heterogeneity. The majority of TNBC cases are characterized by high Ki‐67 expression. TNBC with low Ki‐67 expression accounts for only a small fraction of cases and has been relatively less studied.MethodsThis study analyzed a large single‐center multiomics TNBC data set, combined with a single‐cell data set. The clinical, genomic, and metabolic characteristics of patients with low Ki‐67 TNBC were analyzed.ResultsThe clinical and pathological characteristics were analyzed in 2217 TNBC patients. Low Ki‐67 TNBC was associated with a higher patient age at diagnosis, a lower proportion of invasive ductal carcinoma, increased alterations in the PI3K‐AKT‐mTOR pathway, upregulated lipid metabolism pathways, and enhanced infiltration of M2 macrophages. High Ki‐67 TNBC exhibited a higher prevalence of TP53 gene mutations, elevated nucleotide metabolism, and increased infiltration of M1 macrophages.ConclusionsWe identified specific genomic and metabolic characteristics unique to low Ki‐67 TNBC, which have implications for the development of precision therapies and patient stratification strategies.

Mesothelin- and nucleolin-specific T cells from combined short peptides effectively kill triple-negative breast cancer cells

BackgroundTriple-negative breast cancer (TNBC), known for its aggressiveness and limited treatment options, presents a significant challenge. Adoptive cell transfer, involving the ex vivo generation of antigen-specific T cells from peripheral blood mononuclear cells (PBMCs), emerges as a promising approach. The overexpression of mesothelin (MSLN) and nucleolin (NCL) in TNBC samples underscores their potential as targets for T cell therapy. This study explored the efficacy of multi-peptide pulsing of PBMCs to generate MSLN/NCL-specific T cells targeting MSLN+/NCL+ TNBC cells.MethodsTNBC patient samples were confirmed for both MSLN and NCL expression via immunohistochemistry. Synthesized MSLN and NCL peptides were combined and administered to activate PBMCs from healthy donors. The cancer-killing ability of the resultant T cells was assessed using crystal violet staining, and their subtypes and cytotoxic cytokines were characterized through flow cytometry and cytokine bead array.ResultsFindings showed that 85.3% (127/149) of TNBC cases were positive for either MSLN or NCL, or both; with single positivity rates for MSLN and NCL of 14.1% and 28.9%, respectively. MSLN and NCL peptides, with high binding affinity for HLA-A*02, were combined and introduced to activated PBMCs from healthy donors. The co-pulsed PBMCs significantly induced TEM and TEMRA CD3+/CD8+ T cells and IFN-γ production, compared to single-peptide pulsed or unpulsed conditions. Notably, MSLN/NCL-specific T cells successfully induced cell death in MSLN+/NCL+ MDA-MB-231 cells, releasing key cytotoxic factors such as perforin, granzymes A and B, Fas ligand, IFN-γ, and granulysin.ConclusionsThese findings serve as a proof-of-concept for using multiple immunogenic peptides as a novel therapeutic approach in TNBC patients.

Connexin 43 controls metastatic behavior in triple negative breast cancer through TGFβ1-Smad3-intergin αV signaling axis Based on optical image diagnosis

Abnormal expression of connexin 43 (Cx43) contributes to the development and progression of cancer. However, its regulation is complex and dependent on the environment. The expression of Cx43 in triple-negative cancer lesions was analyzed by immunohistochemistry and optical coherence tomography using experimental models and clinical samples. The model of TGFβ1-SMad3-in-αv signal axis was established and verified by experiments. The results show that Cx43 plays a key role in the regulation of triple-negative cancer metastasis. In vivo, over-expressed Cx43 decreased tumor volume and inhibited ITGαV, TGF-β1, Smad3 and N-cadherin expressions, but enhanced the E-cadherin. Cx43 had the lowest expression in the TNBC samples, especially in lymph node metastatic TNBC patients and had a negative correlation with ITG alpha V, TGF-β1 and Smad3.The study demonstrated Cx43 controlled metastatic behavior through TGF-β1 -Smad3-ITG αV signaling axis in MDA-MB-231 cells, providing evidence for Cx43’s function in TNBC. The optical image diagnosis method can realize the identification and quantitative evaluation of early cancer triple negative, and provide a new strategy and means for the treatment of cancer triple negative.

Huaier-induced suppression of cancer-associated fibroblasts confers immunotherapeutic sensitivity in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is the most intractable subgroup of breast neoplasms due to its aggressive nature. In recent years, immune checkpoint inhibitors (ICIs) have exhibited potential efficacy in TNBC treatment. However, only a limited fraction of patients benefit from ICI therapy, primarily because of the suppressive tumor immune microenvironment (TIME). Trametes robiniophila Murr (Huaier) is a traditional Chinese medicine (TCM) with potential immunoregulatory functions. However, the underlying mechanism remains unclear. PurposeThe present study aimed to investigate the therapeutic role of Huaier in the TIME of TNBC patients. MethodsSingle-cell RNA sequencing (scRNA-seq) was used to systematically analyze the influence of Huaier on the TNBC microenvironment for the first time. The mechanisms of the Huaier-induced suppression of cancer-associated fibroblasts (CAFs) were assessed via real-time quantitative polymerase chain reaction (qRT‒PCR) and western blotting. A tumor-bearing mouse model was established to verify the effects of the oral administration of Huaier on immune infiltration. ResultsUnsupervised clustering of the transcriptional profiles suggested an increase in the number of apoptotic cancer cells in the Huaier group. Treatment with Huaier induced immunological alterations from a "cold" to a "hot" state, which was accompanied by phenotypic changes in CAFs. Mechanistic analysis revealed that Huaier considerably attenuated the formation of myofibroblastic CAFs (myoCAFs) by impairing transforming growth factor-beta (TGF-β)/SMAD signaling. In mouse xenograft models, Huaier dramatically modulated CAF differentiation, thus synergizing with the programmed cell death 1 (PD1) blockade to impede tumor progression. ConclusionsOur findings demonstrate that Huaier regulates cancer immunity in TNBC by suppressing the transition of CAFs to myoCAFs and emphasize the crucial role of Huaier as an effective adjuvant agent in immunotherapy.

Study Reveals a New Approach to Treating Tripple Negative Breast Cancer

riple-negative breast cancer (TNBC) makes up about 15% of all breast cancer cases worldwide. It's particularly hard to treat because it lacks the three common receptors that most therapies target. As a result, most TNBC patients undergo high doses of non-targeted chemotherapy, which often leads to severe side effects such as hair loss, nausea, and pain. The spread of TNBC cells to other organs, such as the brain or lungs, is the main cause of death in patients.

Evaluating interaction between tumor educated platelets and cancer stem cells on breast cancer subtypes.

5 Background: Thrombocytosis has been reported to be responsible for poor prognosis of numerous malignancies. This swarm of platelets acts as foe for the body but as mate for the cancer cells by providing a protective shield around them, helping them to escape immunosurveillance process. A bidirectional interaction between platelets and tumor cells promote their conversion to an activated tumor educated platelet (TEP) state. The present report reveals the critical role played by TEPs to promote metastasis in BC subtypes by interacting with cancer stem cells (CSCs). Methods: Status of intra-tumoral and humoral TEPs (CD41+/CD62P+) was screened in luminal A (LumA) and triple negative (TNBC) BC subgroups. The impact of TEPs on lin-/CD44+/CD24- CSCs of both the categories in-vitro, was deciphered by performing mammosphere assay, clonogeneic and migration assays, with final validation in murine system. Effect on various genes and proteins related to stemness, metastasis and angiogenesis as a result of this interaction was elucidated by RT-PCR, flow cytometry and western blotting. Results: High percentage of TEPs in the peripheral blood is a potential biomarker and responsible for poor prognosis in BC subtypes. Both Lum A and TNBC patients had elevated TEP frequency, compared to healthy blood. Further, patients in the pre-carcinogenic stage had platelet count of >3.5 lakhs. Additionally, screening of breast tumor sections revealed intra-tumoral enrichment of TEPs, comparatively to a greater extent in TNBC than LumA, supporting their role in disease aggression. Also, a positive correlation was noted between TEP and CSC frequencies proving their synergistic interactions. Moreover, in-vitro, TEP influenced CSCs exhibited enormous clonogenic and tumorigenic potentialities. Their metastatic nature was confirmed by their enhanced migratory, invasive, angiogenic capacities with higher VIMENTIN and TWIST along with HIF1α, CD31 and MMP9 expression compared to E-CADHERIN. In line with in-vitro observations, in-vivo too, TEP~CSC produced metastatic colonies in murine lungs. Upon investigation, it was disclosed that it is through WNT-βcatenin-VEGFR2 axis that this mutual interdependency was functioning. Conclusions: This study advocates for the importance of TEPs as potential biomarker in BC diagnosis. Their alliance with vicious CSCs to promote disease advancement acquiesce them as a novel restorative agent.

A preoperative radiogenomic model based on quantitative heterogeneity for predicting outcomes in triple-negative breast cancer patients who underwent neoadjuvant chemotherapy

BackgroundTriple-negative breast cancer (TNBC) is highly heterogeneous, resulting in different responses to neoadjuvant chemotherapy (NAC) and prognoses among patients. This study sought to characterize the heterogeneity of TNBC on MRI and develop a radiogenomic model for predicting both pathological complete response (pCR) and prognosis.Materials and methodsIn this retrospective study, TNBC patients who underwent neoadjuvant chemotherapy at Fudan University Shanghai Cancer Center were enrolled as the radiomic development cohort (n = 315); among these patients, those whose genetic data were available were enrolled as the radiogenomic development cohort (n = 98). The study population of the two cohorts was randomly divided into a training set and a validation set at a ratio of 7:3. The external validation cohort (n = 77) included patients from the DUKE and I-SPY 1 databases. Spatial heterogeneity was characterized using features from the intratumoral subregions and peritumoral region. Hemodynamic heterogeneity was characterized by kinetic features from the tumor body. Three radiomics models were developed by logistic regression after selecting features. Model 1 included subregional and peritumoral features, Model 2 included kinetic features, and Model 3 integrated the features of Model 1 and Model 2. Two fusion models were developed by further integrating pathological and genomic features (PRM: pathology-radiomics model; GPRM: genomics-pathology-radiomics model). Model performance was assessed with the AUC and decision curve analysis. Prognostic implications were assessed with Kaplan‒Meier curves and multivariate Cox regression.ResultsAmong the radiomic models, the multiregional model representing multiscale heterogeneity (Model 3) exhibited better pCR prediction, with AUCs of 0.87, 0.79, and 0.78 in the training, internal validation, and external validation sets, respectively. The GPRM showed the best performance for predicting pCR in the training (AUC = 0.97, P = 0.015) and validation sets (AUC = 0.93, P = 0.019). Model 3, PRM and GPRM could stratify patients by disease-free survival, and a predicted nonpCR was associated with poor prognosis (P = 0.034, 0.001 and 0.019, respectively).ConclusionMultiscale heterogeneity characterized by DCE-MRI could effectively predict the pCR and prognosis of TNBC patients. The radiogenomic model could serve as a valuable biomarker to improve the prediction performance.

Investigating the possible effects of AKT and FAK signaling pathways' inactivation on TNBC cell proliferation and TNBC patients' recurrence free survival via BAG3 regulation

Investigating the possible effects of AKT and FAK signaling pathways' inactivation on TNBC cell proliferation and TNBC patients' recurrence free survival via BAG3 regulation

ASO Visual Abstract: Identifying and Treating Those at Risk-Disparities in Rapid Relapse Among TNBC Patients in the National Cancer Database.

ASO Visual Abstract: Identifying and Treating Those at Risk-Disparities in Rapid Relapse Among TNBC Patients in the National Cancer Database.

Efficacy and prognosis of HER2-Low and HER2-Zero in triple-negative breast cancer after neoadjuvant chemotherapy

Mounting evidence showed that HER2-Low breast cancer patients could benefit from the novel anti-HER2 antibody–drug conjugates (ADCs) treatment, which pointed the way towards better therapy for HER2-Low patients. The purpose of this study was to describe the clinicopathological features, along with chemotherapeutic effects and survival outcomes of HER2-Low and HER2-Zero in TNBC who received neoadjuvant chemotherapy (NACT). We retrospectively evaluated 638 triple-negative breast cancer patients who were treated with neoadjuvant chemotherapy between August 2014 and August 2022. Pathologic complete response (pCR) and survival outcomes were analyzed in HER2-Low cohort, HER2-Zero cohort and the overall patients, respectively. In the entire cohort, 342 (53.6%) patients were HER2-Low and 296 (46.4%) patients were HER2-Zero. No significant difference was found between HER2-Low and HER2-Zero patients based on all the clinical–pathological characteristics. 143 cases (22.4%) achieved pCR after NACT in the overall TNBC patients. The pCR rate of the HER2-Low patients and the HER2-Zero patients was 21.3% and 23.6%, respectively, exhibiting no statistical difference (p = 0.487). The survival of pCR group after NACT significantly improved compared to non-pCR group either in HER2-Low patients or in HER2-Zero patients. Although we found that patients with HER2-Low had longer DFS than patients with HER2-Zero, there was no considerable difference (p = 0.068). However, HER2-Low patients had a dramatically longer OS than HER2-Zero patients (p = 0.012). The data from present study confirmed the clinical importance of HER2-Low expression in TNBC. Further effort is needed to determine whether HER2-Low could be a more favorable prognostic marker for individual treatment.

The Prognostic Impact of HER2-Low and Menopausal Status in Triple-Negative Breast Cancer.

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data on demographics, tumor characteristics, pathologic complete response (pCR) rates and disease-free survival (DFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed. The HER2-low group, compared to the HER2-0 group, showed significantly better DFS, DMFS, OS, BCSS (p = 0.0072, p = 0.0096, p = 0.0180, and p = 0.0001, respectively) with older age and higher rates of postmenopausal status (p < 0.0001). No significant differences in pCR rates were observed. Multivariate analyses identified HER2 status as a significant prognostic factor for DFS (p = 0.048), DMFS (p = 0.018), OS (p = 0.049), and BCSS (p = 0.008). Subgroup analysis revealed that these effects varied with menopausal status, showing more pronounced benefits in postmenopausal women. Our findings suggest that HER2-low TNBC patients exhibit a distinct clinical profile and improved survival compared to HER2-0 TNBC patients, especially in postmenopausal patients. Further research on estrogen and HER2 interaction is needed.

LCP1 correlates with immune infiltration: a prognostic marker for triple-negative breast cancer

ObjectiveTriple-Negative Breast Cancer (TNBC) is known for its aggressiveness and treatment challenges due to the absence of ER, PR, and HER2 receptors. Our work emphasizes the prognostic value of LCP1 (Lymphocyte cytosolic protein 1), which plays a crucial role in cell processes and immune cell activity, to predict outcomes and guide treatments in TNBC.MethodsWe explored LCP1 as a potential biomarker in TNBC and investigated the mRNA and protein expression levels of LCP1. We investigated different databases, including GTEX, TCGA, GEO, cBioPortal and Kaplan-Meier Plotter. Immunohistochemistry on TNBC and benign tumor samples was performed to examine LCP1's relationship with patient clinical characteristics and macrophage markers. We also assessed survival rates, immune cell infiltration, and drug sensitivity related to LCP1 using various bioinformatics tools.ResultsThe results indicated that LCP1 expression was higher in TNBC tissues compared to adjacent normal tissues. However, high expression of LCP1 was significantly associated with favorable survival outcomes in patients with TNBC. Enrichment analysis revealed that genes co-expressed with LCP1 were significantly enriched in various immune processes. LCP1 showed a positive correlation with the infiltration of resting dendritic cells, M1 macrophages, and memory CD4 T cells, and a negative correlation with M2 macrophages. Further analysis suggested a link between high levels of LCP1 and increased survival outcomes in cancer patients receiving immunotherapy.ConclusionLCP1 may serve as a potential diagnostic and prognostic biomarker for TNBC, which was closely associated with immune cell infiltration, particularly M1 and M2 macrophages. Our findings may provide valuable insights into immunotherapeutic strategies for TNBC patients.

Novel insights into paclitaxel’s role on tumor-associated macrophages in enhancing PD-1 blockade in breast cancer treatment

BackgroundTriple-negative breast cancer (TNBC) poses unique challenges due to its complex nature and the need for more effective treatments. Recent studies showed encouraging outcomes from combining paclitaxel (PTX) with programmed...

Advancing targeted combination chemotherapy in triple negative breast cancer: nucleolin aptamer-mediated controlled drug release

BackgroundTriple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil.MethodsWe developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo.ResultsVarious redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo.ConclusionsThis study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.

Shikonin blocks CAF-induced TNBC metastasis by suppressing mitochondrial biogenesis through GSK-3β/NEDD4-1 mediated phosphorylation-dependent degradation of PGC-1α

BackgroundTriple-negative breast cancer (TNBC) is characterized by its high metastatic potential, which results in poor patient survival. Cancer-associated fibroblasts (CAFs) are crucial in facilitating TNBC metastasis via induction of mitochondrial biogenesis. However, how to inhibit CAF-conferred mitochondrial biogenesis is still needed to explore.MethodsWe investigated metastasis using wound healing and cell invasion assays, 3D-culture, anoikis detection, and NOD/SCID mice. Mitochondrial biogenesis was detected by MitoTracker green FM staining, quantification of mitochondrial DNA levels, and blue-native polyacrylamide gel electrophoresis. The expression, transcription, and phosphorylation of peroxisome-proliferator activated receptor coactivator 1α (PGC-1α) were detected by western blotting, chromatin immunoprecipitation, dual-luciferase reporter assay, quantitative polymerase chain reaction, immunoprecipitation, and liquid chromatography-tandem mass spectrometry. The prognostic role of PGC-1α in TNBC was evaluated using the Kaplan–Meier plotter database and clinical breast cancer tissue samples.ResultsWe demonstrated that PGC-1α indicated lymph node metastasis, tumor thrombus formation, and poor survival in TNBC patients, and it was induced by CAFs, which functioned as an inducer of mitochondrial biogenesis and metastasis in TNBC. Shikonin impeded the CAF-induced PGC-1α expression, nuclear localization, and interaction with estrogen-related receptor alpha (ERRα), thereby inhibiting PGC-1α/ERRα-targeted mitochondrial genes. Mechanistically, the downregulation of PGC-1α was mediated by synthase kinase 3β-induced phosphorylation of PGC-1α at Thr295, which associated with neural precursor cell expressed developmentally downregulated 4e1 recognition and subsequent degradation by ubiquitin proteolysis. Mutation of PGC-1α at Thr295 negated the suppressive effects of shikonin on CAF-stimulated TNBC mitochondrial biogenesis and metastasis in vitro and in vivo.ConclusionsOur findings indicate that PGC-1α is a viable target for blocking TNBC metastasis by disrupting mitochondrial biogenesis, and that shikonin merits potential for treatment of TNBC metastasis as an inhibitor of mitochondrial biogenesis through targeting PGC-1α.

Antiapoptotic and Prometastatic Roles of Cytokine FAM3B in Triple-Negative Breast Cancer

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. FAM3B, a secreted protein, has been extensively studied in various types of tumors. However, its function in breast cancer remains poorly understood. MethodsWe analyzed FAM3B expression data from breast cancer patients available at TCGA database and overall survival was analyzed by using the Kaplan-Meier plotter. MDA-MB-231 TNBC tumor cell line and hormone-responsive MCF-7 cell lines were transfected to overexpress FAM3B. We assessed cell death, tumorigenicity, and invasiveness in vitro through MTT analysis, flow cytometry assays, anchorage-independent tumor growth, and wound healing assays, respectively. We performed in vivo evaluation by tumor xenograft in nude mice. ResultsIn silico analysis revealed that FAM3B expression was lower in all breast tumors. However, TNBC patients with high FAM3B expression had a poor prognosis. FAM3B overexpression protected MDA-MB-231 cells from cell death, with increased expression of Bcl-2 and Bcl-xL, and reduced caspase-3 activity. MDA-MB-231 cells overexpressing FAM3B also exhibited increased tumorigenicity and migration rates in vitro, displaying increased tumor growth and reduced survival rates in xenotransplanted nude mice. This phenotype is accompanied by the upregulation of EMT-related genes Slug, Snail, TGFBR2, vimentin, N-cadherin, MMP-2, MMP-9, and MMP-14. However, these effects were not observed in the MCF-7 cells overexpressing FAM3B. ConclusionFAM3B overexpression contributes to tumor growth, promotion of metastasis, and, consequently, leads to a poor prognosis in the most aggressive forms of breast cancer. Future clinical research is necessary to validate FAM3B as both a diagnostic and a therapeutic strategy for TNBC.

Mechanisms underlying neutrophils adhesion to triple-negative breast cancer cells via CD11b-ICAM1 in promoting breast cancer progression

BackgroundTriple-negative breast cancer (TNBC) is recognized as the most aggressive and immunologically infiltrated subtype of breast cancer. A high circulating neutrophil-to-lymphocyte ratio (NLR) is strongly linked to a poor prognosis among patients with breast cancer, emphasizing the critical role of neutrophils. Although the involvement of neutrophils in tumor metastasis is well documented, their interactions with primary tumors and tumor cells are not yet fully understood.MethodsClinical data were analyzed to investigate the role of neutrophils in breast cancer. In vivo mouse model and in vitro co-culture system were used for mechanism researches. Blocking experiments were further performed to identify therapeutic agents against TNBC.ResultsTNBC cells secreted GM-CSF to sustain the survival of mature neutrophils and upregulated CD11b expression. Through CD11b, neutrophils specifically binded to ICAM1 on TNBC cells, facilitating adhesion. Transcriptomic sequencing combined with human and murine functional experiments revealed that neutrophils, through direct CD11b-ICAM1 interactions, activated the MAPK signaling pathway in TNBC cells, thereby enhancing tumor cell invasion and migration. Atorvastatin effectively inhibited ICAM1 expression in tumor cells, and tumor cells with ICAM1 knockout or treated with atorvastatin were unresponsive to neutrophil activation. The MAPK pathway and MMP9 expression were significantly inhibited in the tumor tissues of TNBC patients treated with atorvastatin.ConclusionsTargeting CD11b-ICAM1 with atorvastatin represented a potential clinical approach to reduce the malignant characteristics of TNBC.Graphical

TFAP2A downregulation mediates tumor-suppressive effect of miR-8072 in triple-negative breast cancer via inhibiting SNAI1 transcription

BackgroundTriple-negative breast cancer (TNBC) represents a highly aggressive subset of breast malignancies characterized by its challenging clinical management and unfavorable prognosis. While TFAP2A, a member of the AP-2 transcription factor family, has been implicated in maintaining the basal phenotype of breast cancer, its precise regulatory role in TNBC remains undefined.MethodsIn vitro assessments of TNBC cell growth and migratory potential were conducted using MTS, colony formation, and EdU assays. Quantitative PCR was employed to analyze mRNA expression levels, while Western blot was utilized to evaluate protein expression and phosphorylation status of AKT and ERK. The post-transcriptional regulation of TFAP2A by miR-8072 and the transcriptional activation of SNAI1 by TFAP2A were investigated through luciferase reporter assays. A xenograft mouse model was employed to assess the in vivo growth capacity of TNBC cells.ResultsSelective silencing of TFAP2A significantly impeded the proliferation and migration of TNBC cells, with elevated TFAP2A expression observed in breast cancer tissues. Notably, TNBC patients exhibiting heightened TFAP2A levels experienced abbreviated overall survival. Mechanistically, TFAP2A was identified as a transcriptional activator of SNAI1, a crucial regulator of epithelial-mesenchymal transition (EMT) and cellular proliferation, thereby augmenting the oncogenic properties of TFAP2A in TNBC. Moreover, miR-8072 was unveiled as a negative regulator of TFAP2A, exerting potent inhibitory effects on TNBC cell growth and migration. Importantly, the tumor-suppressive actions mediated by the miR-8072/TFAP2A axis were intricately associated with the attenuation of AKT/ERK signaling cascades and the blockade of EMT processes.ConclusionsOur findings unravel the role and underlying molecular mechanism of TFAP2A in driving tumorigenesis of TNBC. Targeting the TFAP2A/SNAI1 pathway and utilizing miR-8072 as a suppressor represent promising therapeutic strategies for treating TNBC.

Identifying and Treating Those at Risk: Disparities in Rapid Relapse Among TNBC Patients in the National Cancer Database

PurposeThis study was designed to characterize features of rapid relapse TNBC (rrTNBC), an aggressive, poor prognosis breast cancer subset using the National Cancer Database (NCDB).MethodsPatients diagnosed with TNBC between 2010 and 2019 within NCDB were included in analyses. rrTNBC was defined as all-cause mortality ≤24 months from diagnosis. Patient demographic, tumor, and treatment association with rrTNBC were evaluated in univariate, bivariate analyses, and multiple logistic regression models. Two-part models are used to compare receipt of treatment (i.e., receipt of both chemotherapy and breast surgery) versus not in its relationship with rrTNBC.ResultsOverall, 14.5% of patients were categorized as rrTNBC. Age older than 75 years (−41.3%), Black race (−1.4%), Medicare (−2.6%), and Charlson-Deyo score ≥2 (−4.9%) were associated with a lower probability of receiving both chemotherapy and breast surgery. Not receiving both treatments (vs. receiving both chemotherapy and breast surgery) was associated with a two-to-three-fold higher probability of rrTNBC among patients aged older than 75 years (16.6% vs. 6%), having Medicare (3.6% vs. 1.6%), and Charlson-Deyo score ≥2 (16.6% vs. 5.9%).ConclusionsAge, insurance, and comorbidity were related to a lower likelihood of treatment; yet receiving treatment reduced the risk of rrTNBC threefold for each. These findings might be valuable to inform clinical care delivery, as well as future research that examines treatment protocols among diverse patients.