Prognosis Of Triple-negative Breast Cancer Research Articles

CREB-binding protein/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in triple-negative breast cancer.

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated cytotoxic T cells. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.

NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer

Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

Digital Whole Slide Image Analysis of Elevated Stromal Content and Extracellular Matrix Protein Expression Predicts Adverse Prognosis in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and limited treatment options. This study evaluates the prognostic value of stromal markers in TNBC, focusing on the tumor-stroma ratio (TSR) and overall stroma ratio (OSR) in whole slide images (WSI), as well as the expression of type-I collagen, type-III collagen, and fibrillin-1 on tissue microarrays (TMAs), using both visual assessment and digital image analysis (DIA). A total of 101 female TNBC patients, primarily treated with surgery between 2005 and 2016, were included. We found that high visual OSR correlates with worse overall survival (OS), advanced pN categories, lower stromal tumor-infiltrating lymphocyte count (sTIL), lower mitotic index, and patient age (p < 0.05). TSR showed significant connections to the pN category and mitotic index (p < 0.01). High expression levels of type-I collagen (>45%), type-III collagen (>30%), and fibrillin-1 (>20%) were linked to significantly worse OS (p = 0.004, p = 0.013, and p = 0.005, respectively) and progression-free survival (PFS) (p = 0.028, p = 0.025, and p = 0.002, respectively), validated at the mRNA level. Our results highlight the importance of stromal characteristics in promoting tumor progression and metastasis and that targeting extracellular matrix (ECM) components may offer novel therapeutic strategies. Furthermore, DIA can be more accurate and objective in evaluating TSR, OSR, and immunodetected stromal markers than traditional visual examination.

Preliminary Research of Radiolabeled Atezolizumab for the Noninvasive Evaluation of TNBC PD-L1 Expression InVivo.

Programmed death-ligand 1 (PD-L1) expression is related to the efficacy and prognosis in triple-negative breast cancer. This study employed an indirect labeling method to synthesize [125I]PI-Atezolizumab. The invitro stability of [125I]PI-Atezolizumab was assessed through incubation in phosphate buffered saline and fetal bovine serum, revealing sustained stability. Specific binding of [125I]PI-Atezolizumab to MDA-MB-231 cells expressing humanized PD-L1 was assessed through invitro incubation, yielding a Kd value comparable to that of Atezolizumab. This suggests that the labeling process did not compromise the affinity of the Atezolizumab to PD-L1. Subsequently, pharmacokinetic studies were conducted in normal mice and biodistribution experiments in tumor-bearing mice. A comparison of the biodistribution results between [125I]PI-Atezolizumab and 125I-labeled Atezolizumab indicated better invivo stability for the former. Single photon emission computed tomography (SPECT)/CT imaging further confirmed the targeted specificity of [125I]PI-Atezolizumab for PD-L1 in MDA-MB-231 xenografts, which were validated by immunohistochemistry staining. This research underscores the utility of [125I]PI-Atezolizumab, prepared via indirect labeling, for monitoring PD-L1 in triple-negative breast cancer models.

Density Gradient Centrifugation Is an Effective Tool to Isolate Cancer Stem-like Cells from Hypoxic and Normoxia Triple-Negative Breast Cancer Models.

Accumulating evidence has indicated that stemness-related genes are associated with the aggressiveness of triple-negative breast cancer (TNBC). Because no universal markers for breast CSCs are available, we applied the density gradient centrifugation method to enrich breast CSCs. We demonstrated that the density centrifugation method allows for the isolation of cancer stem cells (CSCs) from adherent and non-adherent MCF7 (Luminal A), MDA-MB-231 (TNBC) and MDA-MB-468 (TNBC) breast cancer cells. The current study shows that the CSCs' enriched fraction from Luminal A and TNBC cells have an increased capacity to grow anchorage-independently. CSCs from adherent TNBC are mainly characterized by metabolic plasticity, whereas CSCs from Luminal A have an increased mitochondrial capacity. Moreover, we found that non-adherent growth CSCs isolated from large mammospheres have a higher ability to grow anchorage-independently compared to CSCs isolated from small mammospheres. In CSCs, a metabolic shift towards glycolysis was observed due to the hypoxic environment of the large mammosphere. Using a bioinformatic analysis, we indicate that hypoxia HYOU1 gene overexpression is associated with the aggressiveness, metastasis and poor prognosis of TNBC. An in vitro study demonstrated that HYOU1 overexpression increases breast cancer cells' stemness and hyperactivates their metabolic activity. In conclusion, we show that density gradient centrifugation is a non-marker-based approach to isolate metabolically flexible (normoxia) CSCs and glycolytic (hypoxic) CSCs from aggressive TNBC.

Prognostic risk model under the immune-associated long chain non-coding ribonucleic acid and its application in survival prognosis assessment of patients with breast cancer

This study aimed to develop a prognostic risk model based on immune-related long non-coding RNAs (lncRNAs). By analyzing the expression profiles of specific long non-coding RNAs, the objective was to construct a predictive model to accurately assess the survival prognosis of breast cancer (BC) patients. This effort seeks to provide personalized treatment strategies for patients and improve clinical outcomes. Based on the median risk value, 300 samples of triple-negative BC (TNBC) patients were rolled into a high-risk group (HR group, n = 140) and a low-risk group (LR group, n = 160). Multivariate Cox (MVC) analysis was performed by combining the patient risk score and clinical information to evaluate the prognostic value of the prognostic risk (PR) model. A total of 371 immune-related lncRNAs associated with the prognosis of TNBC were obtained from 300 TNBC samples. Nine associated with prognosis were obtained by univariate Cox (UVC) analysis, and 3 (AC090181.2, LINC01235, and LINC01943) were selected by MVC analysis for the construction of TNBC PR model. Survival analysis showed a great difference in TNBC patients in different groups (P < 0.001). The receiver operator characteristic (ROC) curve showed the model possessed a good area under ROC curve (AUC), which was 0.928. The patient RS jointing with clinical information as well as the MVC analysis revealed that RS was an independent risk factor (IRF) for prognosis of TNBC (P < 0.05, HR = 1.033286). Therefore, the lncRNAs associated with TNBC immunity can be screened by bioinformatics analysis, and the established PR model of TNBC could better predict the prognosis of patients with TNBC, exhibiting a high application value in clinic.

Advances in siRNA Drug Delivery Strategies for Targeted TNBC Therapy.

Among breast cancers, triple-negative breast cancer (TNBC) has been recognized as the most aggressive type with a poor prognosis and low survival rate. Targeted therapy for TNBC is challenging because it lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Chemotherapy, radiation therapy, and surgery are the common therapies for TNBC. Although TNBC is prone to chemotherapy, drug resistance and recurrence are commonly associated with treatment failure. Combination therapy approaches using chemotherapy, mAbs, ADC, and antibody-siRNA conjugates may be effective in TNBC. Recent advances with siRNA-based therapy approaches are promising for TNBC therapy with better prognosis and reduced mortality. This review discusses advances in nanomaterial- and nanobiomaterial-based siRNA delivery platforms for TNBC therapy exploring targeted therapy approaches for major genes, proteins, and TFs upregulated in TNBC tumors, which engage in molecular pathways associated with low TNBC prognosis. Bioengineered siRNA drugs targeting one or several genes simultaneously can downregulate desired genes, significantly reducing disease progression.

Association of clinicopathologic and sonographic features with stromal tumor-infiltrating lymphocytes in triple-negative breast cancer

BackgroundIncreased level of stromal tumor-infiltrating lymphocytes (sTILs) are associated with therapeutic outcomes and prognosis in triple-negative breast cancer (TNBC). This study aimed to investigate the associations of clinicopathologic and sonographic features with sTILs level in TNBC.MethodsThis study included invasive TNBC patients with postoperative evaluation of sTILs after surgical resection. Tumor shape, margin, orientation, echo pattern, posterior features, calcification, and vascularity were retrospectively evaluated. The patients were categorized into high-sTILs (≥ 20%) and low-sTILs (< 20%) level groups. Chi-square or Fisher’s exact tests were used to assess the association of clinicopathologic and sonographic features with sTILs level.ResultsThe 171 patients (mean ± SD age, 54.7 ± 10.3 years [range, 22‒87 years]) included 58.5% (100/171) with low-sTILs level and 41.5% (71/171) with high-sTILs level. The TNBC tumors with high-sTILs level were more likely to be no special type invasive carcinoma (p = 0.008), higher histologic grade (p = 0.029), higher Ki-67 proliferation rate (all p < 0.05), and lower frequency of associated DCIS component (p = 0.026). In addition, the TNBC tumors with high-sTILs level were more likely to be an oval or round shape (p = 0.001), parallel orientation (p = 0.011), circumscribed or micro-lobulated margins (p < 0.001), complex cystic and solid echo patterns (p = 0.001), posterior enhancement (p = 0.002), and less likely to have a heterogeneous pattern (p = 0.001) and no posterior features (p = 0.002).ConclusionsThis preliminary study showed that preoperative sonographic characteristics could be helpful in distinguishing high-sTILs from low-sTILs in TNBC patients.

Impact of microRNA variants on PI3K/AKT signaling in triple-negative breast cancer: comprehensive review.

Breast cancer (BC) is a significant cause of cancer-related mortality, and triple-negative breast cancer (TNBC) is a particularly aggressive subtype associated with high mortality rates, especially among younger females. TNBC poses a considerable clinical challenge due to its aggressive tumor behavior and limited therapeutic options. Aberrations within the PI3K/AKT pathway are prevalent in TNBC and correlate with increased therapeutic intervention resistance and poor outcomes. MicroRNAs (miRs) have emerged as crucial PI3K/AKT pathway regulators influencing various cellular processes involved in TNBC pathogenesis. The levels of miRs, including miR-193, miR-4649-5p, and miR-449a, undergo notable changes in TNBC tumor tissues, emphasizing their significance in cancer biology. This review explored the intricate interplay between miR variants and PI3K/AKT signaling in TNBC. The review focused on the molecular mechanisms underlying miR-mediated dysregulation of this pathway and highlighted specific miRs and their targets. In addition, we explore the clinical implications of miR dysregulation in TNBC, particularly its correlation with TNBC prognosis and therapeutic resistance. Elucidating the roles of miRs in modulating the PI3K/AKT signaling pathway will enhance our understanding of TNBC biology and unveil potential therapeutic targets. This comprehensive review aims to discuss current knowledge and open promising avenues for future research, ultimately facilitating the development of precise and effective treatments for patients with TNBC.

Scutellaria barbata D.Don and Scleromitrion diffusum (Willd.) R.J.Wang inhibits the progression of triple negative breast cancer though the activation inhibition of NF-κB triggered by CAFs-derived IL6

Ethnopharmacological relevanceThe treatment options for triple-negative breast cancer (TNBC) are limited. Traditional Chinese Medicine (TCM) plays an important role in the treatment of TNBC. The herb pair Scutellaria barbata D.Don and Scleromitrion diffusum (Willd.) R.J.Wang (SH) is commonly used in clinical practice for its anti-tumor properties. It has been proven to have good therapeutic effects on tumor-related diseases, but the underlying molecular mechanisms are not yet fully explained. Aim of studyThrough bioinformatics, it was validated that IL6, primarily derived from cancer-associated fibroblasts (CAFs), is associated with poor prognosis. Additionally, cell and animal experiments confirmed that SH inhibits tumor proliferation, migration, and growth in an orthotopic tumor model by suppressing the IL6/NF-κB pathway. Materials and methodsGEO, TCGA and HPA databases were used to analyze the prognostic value of CAFs and IL6, then IL6 resource was detected. After the bioinformatics, the influence of CAFs and CAFs-derived IL6 on TNBC was verified by experiments both in vitro and in vivo. Cell clone formation assay, wound-Healing assay, and Transwell assay were used to detect the promotion of CAFs and CAFs-derived IL6 and the inhibition of SH in vitro. TNBC model in mice was used to prove the promotion of CAFs and CAFs-derived IL6 and the inhibition of SH in vivo. The biological pathway of NF-κB was explored by western blotting through detecting unique molecules. ResultsBioinformatics analysis revealed that higher proportion of CAFs and elevated level of IL6 were significantly associated with poor prognosis in TNBC. At the same time, IL6 was proved predominantly derived from CAFs. After the indication of bioinformatics, experiments in vitro demonstrated that both CAFs and IL6 could enhance the clone formation and migration ability of MDA-MD-231 cells (231), furthermore, the promotion of CAFs was related with the level of IL6. Based on these data, mechanism was detected that CAFs-derived IL6 enhancement was closely related to the activation of NF-κB signaling pathway, while the activation can be reduced by SH. In the end, the promotion of CAFs/CAFs-derived IL6/NF-κB and the efficacy of SH inhibition were both confirmed by experiments in vivo. ConclusionsBioinformatics data indicates that higher proportion of CAFs and higher level of CAFs-derived IL6 are significantly related to poorer survival of TNBC. CAFs and CAFs-derived IL6 were proved to promote the progression of TNBC both in vitro and in vivo, and the process of which was significantly related to the activation of NF-κB. SH inhibited the progress of TNBC, which was proved to be closely related to CAFs/CAFs-derived IL6/NF-κB.

The Conflicting Prognostic Role of the Stroma–Tumor Ratio in Breast Cancer Molecular Subtypes

The tumor microenvironment plays a key role in tumor progression. The proportion of the stroma-to-tumor cells (stroma-tumor ratio [STR]) has a variable prognostic significance in breast cancer (BC) molecular classes. In this study, we evaluated the mechanisms of stroma formation and composition in different molecular subtypes, which could explain the different prognostic values. This study interrogated 2 large well-characterized BC cohorts. Firstly, an in-house BC cohort (n = 822) encompassing all BC molecular subtypes from the Nottingham series was used. In each subtype, stromal assessment was carried out, and tumors were assigned to 2 groups: high and low STR, and further correlation with tumor characteristics and patient outcomes was investigated. The contribution of tumor-infiltrating lymphocytes (TILs) to the stroma has also been studied. Secondly, the public domain data set (The Cancer Genome Atlas data [TCGA], n = 978) was used as a validation cohort and for differential gene expression (DGE) analysis. DGE was performed to identify a set of genes associated with high STR in the 3 main molecular subtypes. High STR was associated with favorable patient outcomes in the whole cohort and in the luminal subtype, whereas high STR showed an association with poor outcomes in triple-negative BC (TNBC). No association with outcome was found in the HER2 enriched BC. DGE analysis identified various pathways in luminal and TNBC subtypes, with immune upregulation and hypoxia pathways enriched in TNBC, and pathways related to fibrosis and stromal remodeling enriched in the luminal group instead. Low STR accompanied by high TILs was shown to carry the most favorable prognosis in TNBC. In line with the DGE results, TILs played a major prognostic role in the stroma of TNBC but not in the luminal or HER2-enriched subtypes. The underlying molecular mechanisms and composition of the stroma in BC are variable in the molecular subtypes and explain the difference in its prognostic significance.

High Caveolin-1 mRNA expression in triple-negative breast cancer is associated with an aggressive tumor microenvironment, chemoresistance, and poor clinical outcome.

Currently, there are few treatment-predictive and prognostic biomarkers in triple-negative breast cancer (TNBC). Caveolin-1 (CAV1) is linked to chemoresistance and several important processes involved in tumor progression and metastasis, such as epithelial-mesenchymal transition (EMT). Herein, we report that high CAV1 gene expression is an independent factor of poor prognosis in TNBC. CAV1 gene expression was compared across different molecular features (e.g., PAM50 subtypes). CAV1 expression was assessed in relation to clinical outcomes using Cox regression adjusted for clinicopathological predictors. Differential gene expression and gene set enrichment analyses were applied to compare high- and low-expressing CAV1 tumors. Tumor microenvironment composition of high- and low-expressing CAV1 tumors was estimated using ECOTYPER. Tumor tissue microarrays were used to evaluate CAV1 protein levels in stromal and malignant cells. In the SCAN-B (n = 525) and GSE31519 (n = 327) cohorts, patients with CAV1-high tumors had an increased incidence of early recurrence adjusted HR 1.78 (95% CI 1.12-2.81) and 2.20 (95% CI 1.39-3.47), respectively. In further analysis, high CAV1 gene expression was associated with a molecular profile indicating altered metabolism, neovascularization, chemoresistance, EMT, suppressed immune response, and active tumor microenvironment. Protein levels of CAV1 in malignant and stromal cells were not correlated with CAV1 gene expression. CAV1 gene expression in TNBC is a biomarker that merits further investigation in clinical trials and as a therapeutic target.

Baohuoside I chemosensitises breast cancer to paclitaxel by suppressing extracellular vesicle/CXCL1 signal released from apoptotic cells.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and chemotherapy is the cornerstone treatment for TNBC. Regrettably, emerging findings suggest that chemotherapy facilitates pro-metastatic changes in the tumour microenvironment. Extracellular vesicles (EVs) have been highly implicated in cancer drug resistance and metastasis. However, the effects of the EVs released from dying cancer cells on TNBC prognosis and corresponding therapeutic strategies have been poorly investigated. This study demonstrated that paclitaxel chemotherapy elicited CXCL1-enriched EVs from apoptotic TNBC cells (EV-Apo). EV-Apo promoted the chemoresistance and invasion of co-cultured TNBC cells by polarizing M2 macrophages through activating PD-L1 signalling. However, baohuoside I (BHS) remarkably sensitized the co-cultured TNBC cells to paclitaxel chemotherapy via modulating EV-Apo signalling. Mechanistically, BHS remarkably decreased C-X-C motif chemokine ligand 1 (CXCL1) cargo within EV-Apo and therefore attenuated macrophage M2 polarization by suppressing PD-L1 activation. Additionally, BHS decreased EV-Apo release by diminishing the biogenesis of intraluminal vesicles (ILVs) within multivesicular bodies (MVBs) of TNBC cells. Furthermore, BHS bound to the LEU104 residue of flotillin 2 (FLOT2) and interrupted its interaction with RAS oncogene family member 31 (RAB31), leading to the blockage of RAB31-FLOT2 complex-driven ILV biogenesis. Importantly, BHS remarkably chemosensitised paclitaxel to inhibit TNBC metastasis in vivo by suppressing EV-ApoCXCL1-induced PD-L1 activation and M2 polarization of tumour-associated macrophages (TAMs). This pioneering study sheds light on EV-ApoCXCL1 as a novel therapeutic target to chemosensitise TNBC, and presents BHS as a promising chemotherapy adjuvant to improve TNBC chemosensitivity and prognosis by disturbing EV-ApoCXCL1 biogenesis.

Inhibition of ABI2 ubiquitination-dependent degradation suppresses TNBC cell growth via down-regulating PI3K/Akt signaling pathway

Triple negative breast cancer (TNBC) is a type of cancer that lacks receptor expression and has complex molecular mechanisms. Recent evidence shows that the ubiquitin-protease system is closely related to TNBC. In this study, we obtain a key ubiquitination regulatory substrate-ABI2 protein by bioinformatics methods, which is also closely related to the survival and prognosis of TNBC. Further, through a series of experiments, we demonstrated that ABI2 expressed at a low level in TNBC tumors, and it has the ability to control cell cycle and inhibit TNBC cell migration, invasion and proliferation. Molecular mechanism studies proved E3 ligase CBLC could increase the ubiquitination degradation of ABI2 protein. Meanwhile, RNA-seq and IP experiments indicated that ABI2, acting as a crucial factor of tumor suppression, can significantly inhibit PI3K/Akt signaling pathway via the interaction with Rho GTPase RAC1. Finally, based on TNBC drug target ABI2, we screened and found that FDA-approved drug Colistimethate sodium(CS) has significant potential in suppressing the proliferation of TNBC cells and inducing cell apoptosis, making it a promising candidate for impeding the progression of TNBC.

FOXCUT regulates the malignant phenotype of triple-negative breast Cancer via the miR-337-3p/ANP32E Axis

BackgroundThe lack of specific molecular targets and the rapid spread lead to a worse prognosis of triple-negative breast cancer (TNBC). Therefore, identifying new therapeutic and prognostic biomarkers helps to develop effective treatment strategies for TNBC. MethodsThrough preliminary bioinformatics analysis, FOXCUT was found to be significantly overexpressed in breast cancer, especially in TNBC. Tissue samples were collected from 15 TNBC patients, and qRT-PCR was employed to validate the expression of FOXCUT in both TNBC patient tissues and TNBC cell lines. We also carried out the GSEA analysis and KEGG enrichment analysis of FOXCUT. Additionally, the effects of FOXCUT knockdown on TNBC cell malignant behaviors, and aerobic glycolysis were assessed by methods including CCK-8, Transwell, western blot, and Seahorse XF 96 analyses. Moreover, utilizing databases predicting interactions between ceRNAs, corresponding lncRNA-miRNA binding relationships, and miRNA-mRNA interactions were predicted. These predictions were subsequently validated through RNA immunoprecipitation and dual-luciferase reporter assays. ResultsFOXCUT exhibited high expression in both TNBC tissues and cell lines, fostering cell malignant behaviors and glycolysis. FOXCUT was found to sponge miR-337-3p, while miR-337-3p negatively regulated the expression of ANP32E. Consequently, FOXCUT ultimately facilitated the malignant phenotype of TNBC by upregulating ANP32E expression. ConclusionThis study elucidated the role of FOXCUT in elevating aerobic glycolysis levels in TNBC and driving malignant cancer cell development via the miR-337-3p/ANP32E regulatory axis.

Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy

BackgroundPaclitaxel (PTX) treatment resistance is an important factor leading to poor prognosis in triple-negative breast cancer (TNBC), therefore there is an urgent need to identify new target for combination therapy. Neddylation is a post-translational process that introduces a ubiquitin-like protein called neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Previous studies have found that neddylation is activated in multiple tumors, but its relationship with PTX chemotherapy sensitivity has not been reported.MethodsDifferences in UBC12 and NEDD8 expression levels between PTX-sensitive and PTX-insensitive TNBC tissues were validated using public databases and immunohistochemistry. The in vitro and in vivo functional experiments were used to observe the effect of neddylation inhibition combined with PTX therapy on tumor progression. Co-IP, western blot and PCR assays were used to investigate the molecular mechanisms. Molecular docking was used to simulate the protein binding of UBC12 and TRIM25. Molecular dynamics simulation was used to observe the changes in TRIM25 protein conformation.ResultsWe found that in TNBC that is insensitive to PTX, NEDD8 and NEDD8 conjugating enzyme UBC12 are highly expressed. Treatment with the NEDD8-activating enzyme (NAE) inhibitor mln4924 or knockdown of UBC12 significantly increased the sensitivity of the tumor to PTX, and this increase in sensitivity is related to UBC12-mediated autophagy activation. Mechanistically, UBC12 can transfer NEDD8 to E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) at K117. Molecular dynamics simulations indicate that the neddylation modification of TRIM25 reduces steric hindrance in its RING domain, facilitating the binding of TRIM25 and ubiquitylated substrates. Subsequently, TRIM25 promotes the nuclear translocation of transcription factor EB (TFEB) and transcription of autophagy related genes by increasing K63-polyubiquitination of TFEB, thereby reducing tumor sensitivity to PTX.ConclusionsNeddylation is activated in PTX-insensitive TNBC. Specifically, autophagy gene transcriptional activation mediated by the UBC12/TRIM25/TFEB axis reduces TNBC sensitivity to PTX. Neddylation suppression combination with PTX treatment shows a synergistic anti-tumor effect.

IRE1α inhibitor enhances paclitaxel sensitivity of triple-negative breast cancer cells.

Breast cancer is the most commonly diagnosed cancer in women, and triple-negative breast cancer (TNBC) accounts for approximately 15%-20% of all breast cancers. TNBC is highly invasive and malignant. Due to the lack of relevant receptor markers, the prognosis of TNBC is poor and the five-year survival rate is low. Paclitaxel is the first-line drug for the treatment of TNBC, which can inhibit cell mitosis. However, many patients develop drug resistance during treatment, leading to chemotherapy failure. Therefore, finding new therapeutic combinations to overcome TNBC drug resistance can provide new strategies for improving the survival rate of TNBC patients. Cell viability assay, RT-qPCR, Colony formation assay, Western blot, and Xenogeneic transplantation methods were used to investigate roles and mechanisms of IRE1α/XBP1s pathway in the paclitaxel-resistant TNBC cells, and combined paclitaxel and IRE1α inhibitor in the treatment of TNBC was examined in vitro and in vivo. We found activation of UPR in paclitaxel-resistant cells, confirming that IRE1α/XBP1 promotes paclitaxel resistance in TNBC. In addition, we demonstrated that the combination of paclitaxel and IRE1α inhibitors can synergistically inhibit the proliferation of TNBC tumors both in vitro and in vivo,suggesting that IRE1α inhibitors combined with paclitaxel may be a new treatment option for TNBC. In this study, we demonstrated the important role of IRE1α signaling in mediating paclitaxel resistance and identified that combination therapies targeting IRE1α signaling could overcome paclitaxel resistance and enhance chemotherapy efficacy.

Quantifying spatial CXCL9 distribution with image analysis predicts improved prognosis of triple-negative breast cancer.

Background: The C-X-C motif chemokine ligand 9 (CXCL9) plays a pivotal role in tumor immunity by recruiting and activating immune cells. However, the relationship between CXCL9 expression and prognosis in triple-negative breast cancer (TNBC) is unclear. Methods: We investigated CXCL9 mRNA expression, clinicopathological features, and prognosis in TNBC patients. We also used computational image analysis to quantify and assess the distribution of CXCL9 protein in the tumor core (TC) and invasive margin (IM). Results: CXCL9 mRNA expression was significantly higher in TNBC tumors compared to normal tissue (p < 0.001) and was associated with smaller tumors (p = 0.022) and earlier stages (p = 0.033). High CXCL9 mRNA expression was correlated with improved overall survival (OS) in three independent cohorts (all p < 0.05). In a separate analysis, low CXCL9 protein expression was associated with increased lymph node metastasis (p = 0.018 and p = 0.036). High CXCL9 protein expression in the TC, IM, or both was associated with prolonged OS (all p < 0.001). Conclusion: High CXCL9 expression, at both the mRNA and protein levels, is associated with improved prognosis in TNBC patients. CXCL9 expression in the TC and/or IM may be an independent prognostic factor.

Triple-negative breast cancer survival prediction: population-based research using the SEER database and an external validation cohort.

Triple-negative breast cancer (TNBC) is linked to a poorer outlook, heightened aggressiveness relative to other breast cancer variants, and limited treatment choices. The absence of conventional treatment methods makes TNBC patients susceptible to metastasis. The objective of this research was to assess the clinical and pathological traits of TNBC patients, predict the influence of risk elements on their outlook, and create a prediction model to assist doctors in treating TNBC patients and enhancing their prognosis. We included 23,394 individuals with complete baseline clinical data and survival information who were diagnosed with primary TNBC between 2010 and 2015 based on the SEER database. External validation utilised a group from The Affiliated Lihuili Hospital of Ningbo University. Independent risk factors linked to TNBC prognosis were identified through univariate, multivariate, and least absolute shrinkage and selection operator regression methods. These characteristics were chosen as parameters to develop 3- and 5-year overall survival (OS) and breast cancer-specific survival (BCSS) nomogram models. Model accuracy was assessed using calibration curves, consistency indices (C-indices), receiver operating characteristic curves (ROCs), and decision curve analyses (DCAs). Finally, TNBC patients were divided into groups of high, medium, and low risk, employing the nomogram model for conducting a Kaplan-Meier survival analysis. In the training cohort, variables such as age at diagnosis, marital status, grade, T stage, N stage, M stage, surgery, radiation, and chemotherapy were linked to OS and BCSS. For the nomogram, the C-indices stood at 0.762, 0.747, and 0.764 in forecasting OS across the training, internal validation, and external validation groups, respectively. Additionally, the C-index values for the training, internal validation, and external validation groups in BCSS prediction stood at 0.793, 0.755, and 0.811, in that order. The findings revealed that the calibration of our nomogram model was successful, and the time-variant ROC curves highlighted its effectiveness in clinical settings. Ultimately, the clinical DCA showcased the prospective clinical advantages of the suggested model. Furthermore, the online version was simple to use, and nomogram classification may enhance the differentiation of TNBC prognosis and distinguish risk groups more accurately. These nomograms are precise tools for assessing risk in patients with TNBC and forecasting survival. They can help doctors identify prognostic markers and create more effective treatment plans for patients with TNBC, providing more accurate assessments of their 3- and 5-year OS and BCSS.

The potential mechanism of HIF-1α and CD147 in the development of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis, and the outcomes of common therapy were not favorable. The samples of 84 patients with TNBC and 40 patients with breast fibroadenoma were collected in the pathology department specimen library of our hospital. The prognosis of patients was obtained through outpatient follow-up information, telephone and WeChat contacts, and medical records. The mRNA expression was analyzed using bioinformation and quantitative real-time polymerase chain reaction (qPCR). The protein expression was determined by hematoxylin-eosin staining and immunohistochemical staining. The results of survival analysis were visualized using Kaplan-Meier curves. The immunohistochemical staining showed that hypoxia-inducible factor-1alpha (HIF-1α) was mainly distributed in the nucleus and cytoplasm, while CD147 is mainly distributed in cell membrane and cytoplasm. The qPCR results exhibited that the expression level of HIF-1α and CD147 in TNBC tissue was significantly higher than that in breast fibroadenoma tissue. The expression of HIF-1α was related to the histological grade and lymph node metastasis in TNBC, and the expression of CD147 was related to Ki-67, histological grade and lymph node metastasis. There was a positive relationship between the expression of CD147 and HIF-1α. The upregulated expression of CD147 was closely related to the poor prognosis of OS in TNBC. CD147 could be a biomarker for the prognosis of TNBC and closely related to the expression of HIF-1α.