Target For Triple-negative Breast Cancer Research Articles

A chemo/chemodynamic nanoparticle based on hyaluronic acid induces ferroptosis and apoptosis for triple-negative breast cancer therapy

Triple-negative breast cancer (TNBC) poses a serious threat to women's life and health due to its high malignancy, strong invasiveness, and propensity for early recurrence and metastasis. Therefore, there is an urgent need to develop a highly effective and low-toxic TNBC treatment scheme to enhance the anti-cancer efficacy and prolong the survival of patients. In this work, we designed and synthesized a chemodynamic therapy (CDT) agent (HA-Fc-Mal). The chemo/chemodynamic (CT/CDT) nanoparticle (HCM@DOX) based on hyaluronic acid induces ferroptosis and apoptotic for TNBC therapy was constructed via self-assembled of HA-Fc-Mal and doxorubicin (DOX). HCM@DOX orderly realized the TNBC targeting, controlled DOX release, GSH depletion and induce ROS erupt. In vivo and in vitro experiments confirmed that HCM@DOX inhibited the growth of 4 T1 tumors through ferroptosis and apoptosis, and the tumor inhibition rate was as high as 81.87 %. In addition, HCM@DOX significantly inhibited lung metastasis and exhibited excellent biosafety. Overall, our findings offer a new strategy for TNBC therapy using a CT/CDT nanoparticle that induces ferroptosis and apoptosis.

Long noncoding RNA LINC00885 upregulates NCK1 to promote cell viability and migration of triple-negative breast cancer cells through sponging miR-654-3p.

LINC00885 is a novel oncogenic long noncoding RNA (LncRNA) which is upregulated in various types of cancer, but its function in triple-negative breast cancer (TNBC) remains unknown. This study aimed to determine the role of LINC00885 on TNBC development. Clinical interrelation and survival analysis were determined using online database. The CCK-8 and Transwell assays were used to detect the proliferation and migration behaviors in TNBC cell lines. The interaction among genes was detected by RNA pull down assay. LncRNA LINC00885 was highly expressed in TNBC compared to normal breast like. Low levels of LINC00885 was related to good prognosis in TNBC patients compared to TNBC patients with high LINC00885. LINC00885-downregulation inhibited, whereas LINC00885-overexpression promoted the proliferation and migration capability of TNBC cell lines. In TNBC cell lines, noncatalytic region of tyrosine kinase 1 (NCK1) expression was positively associated with LINC00885 expression, and shRNA-mediated the depletion of NCK1 significantly abolished LINC00885 upregulation-mediated pro-tumor effects. Combined with online databases, miR-654-3p was screened as the direct target gene of LINC00885, which could directly bind to 3'-untranslated regions (3'-UTR) of NCK1, resulting in the decreased expression of NCK1 in TNBC cell lines. LINC00885 overexpression-mediated the upregulation of NCK1 was abrogated by miR-654-3p mimics. MiR-654-3p mimics significantly rescued the tumor promotive role caused by LINC00885-overexpression. However, exogenous NCK1 notably eliminated the anti-tumor effects caused by miR-654-3p mimics in LINC00885-overexpressed cells. LINC00885 is expressed at a high level in TNBC. LINC00885 promoted proliferation and migration by regulating the miR-654-3p/NCK1 axis in TNBC cell lines. Possibly, LINC00885 can be served as a potential therapeutic target for TNBC.

The use of MFAP2 for diagnosis, prognosis and immunotherapy of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is characterized by significant heterogeneity, presenting a formidable challenge with a poor prognosis and a deficiency of efficacious treatment options. In this comprehensive study, we investigated the multifaceted role of Microfibril-associated glycoprotein 2 (MFAP2) in TNBC using a combination of bioinformatics analysis involving Gene Expression Omnibus (GEO), OncoDB, UALCAN, Human Protein Atlas (HPA), TIMER, STRING, DAVID, and GSCA databases and in vitro experiments, such as cell culture, MFAP2 gene knockdown, RT-qPCR, western Blot, colony formation, Cell counting kit-8, and wound healing assays. Our findings demonstrated a significant up-regulation of MFAP2 mRNA in TNBC cell lines, emphasizing its potential as a diagnostic biomarker. Validation across multiple datasets further affirmed the elevated expression of MFAP2 in TNBC tissues, underscoring its prognostic relevance. Notably, our study revealed a correlation between MFAP2 expression and immune cell infiltration, suggesting its role in shaping the tumor microenvironment. STRING analysis unveiled interactions with proteins involved in elastic fibers and extracellular matrix constituents. Furthermore, KEGG pathway analysis highlighted enrichment in the TGF-beta signaling pathway, implicating MFAP2 in key cancer-related processes. Drug sensitivity analysis identified potential therapeutic targets, supporting MFAP2's utility in personalized treatment strategies. In vitro experiments corroborated the oncogenic impact of MFAP2, demonstrating its influence on TNBC cell proliferation and migration. These comprehensive findings position MFAP2 as a promising biomarker and therapeutic target in TNBC, offering valuable insight for future research and clinical application.

Homologous-targeting biomimetic nanoparticles co-loaded with melittin and a photosensitizer for the combination therapy of triple negative breast cancer.

Melittin (Mel) is considered a promising candidate drug for the treatment of triple negative breast cancer (TNBC) due to its various antitumor effects. However, its clinical application is hampered by notable limitations, including hemolytic activity, rapid clearance, and a lack of tumor selectivity. Here, we designed novel biomimetic nanoparticles based on homologous tumor cell membranes and poly(lactic-co-glycolic acid) (PLGA)/poly(beta-aminoester) (PBAE), denoted MDM@TPP, which efficiently coloaded the cytolytic peptide Mel and the photosensitizer mTHPC. Both in vitro and in vivo, the MDM@TPP nanoparticles effectively mitigated the acute toxicity of melittin and exhibited strong TNBC targeting ability due to the homologous targeting effect of the tumor cell membrane. Under laser irradiation, the MDM@TPP nanoparticles showed excellent photodynamic performance and thus accelerated the release of Mel by disrupting cell membrane integrity. Moreover, Mel combined with photodynamic therapy (PDT) can synergistically kill tumor cells and induce significant immunogenic cell death, thereby stimulating the maturation of dendritic cells (DCs). In 4T1 tumor-bearing mice, MDM@TPP nanoparticles effectively inhibited the growth and metastasis of primary tumors and finally prevented tumor recurrence by improving the immune response.

CircBRAF promotes the progression of triple-negative breast cancer through modulating methylation by recruiting KDM4B to histone H3K9me3 and IGF2BP3 to mRNA.

Understanding the molecular characteristics of triple-negative breast cancer (TNBC) and developing more tailored treatment approaches is crucial. Circular RNAs (circRNAs), as potential therapeutic targets, remain largely unexplored in TNBC. This study utilized circRNA microarray analysis to determine the expression of circRNAs in TNBC, analyzing nine patient specimens. The characteristics of circBRAF were examined using divergent PCR primers, Sanger sequencing, fluorescence in situ hybridization (FISH) analysis, and the application of RNase and actinomycin D. The biological function of circBRAF in TNBC was further investigated through colony formation, tube formation, and transwell assays. Crucially, the mechanisms underlying the effects of circBRAF on TNBC progression were explored via RNA immunoprecipitation sequencing (RIP-seq) data, MS2 pulldown, RNA sequencing (RNA-seq) analysis, circBRAF knockdown, histone H3K9me3 modification, and Chromatin Isolation by RNA Purification (ChIRP) tests followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We focused particularly on hsa_circ_0007178, produced from exons 4-13 of the oncogene BRAF. Functional experiments revealed that circBRAF is crucial for the development of TNBC, with its knockdown preventing angiogenesis, metastasis, and cell division in vitro. Mechanistically, circBRAF interacts with KDM4B and IGF2BP3, promoting TNBC growth. Interaction of circBRAF with IGF2BP3 increased the expression of VCAN, FN1, CDCA3, or B4GALT3 by controlling mRNA stability through RNA N6-methyladenosine (m6A) modification. Furthermore, circBRAF upregulated the expression of ADAMTS14 and MMP9 through recruitment of KDM4B to enhance respective H3K9me3 modification. Furthermore, overexpression of circBRAF was able to overcome the inhibitory effects of siKDM4B and siIGF2BP3 on cell migration and invasion. Our findings suggest that circBRAF may act as an oncogene in TNBC through its specific interactions with KDM4B and IGF2BP3, implying that circBRAF could serve as a potentially effective novel therapeutic target for TNBC.

A novel antagonist of the CCL5/CCR5 axis suppresses the tumor growth and metastasis of triple-negative breast cancer by CCR5-YAP1 regulation

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with a high mortality rate, and few effective therapeutic strategies are available. CCL5/CCR5 is an appealing immunotherapeutic target for TNBC. However, its signaling mechanism is poorly understood and its direct antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a more selective and potent antagonist than the known CCR5 antagonist maraviroc. Without photodynamic therapy, verteporfin demonstrated significant inhibition on TNBC tumor growth through immune regulation, remarkable suppression of lung metastasis by cell-intrinsic mechanism, and a significant extension of overall survival in vivo. Mechanistically, CCR5 was found to be essential for expression of the key hippo effector YAP1. It promoted YAP1 transcription via HIF-1α and exerted further control over the migration of CD8+ T, NK, and MDSC immune cells through chemokines CXCL16 and CXCL8 which were identified from RNA-seq. Moreover, the CCR5-YAP1 axis played a vital role in promoting metastasis by modulating β-catenin and core epithelial-mesenchymal transition transcription factors ZEB1 and ZEB2. It is noteworthy that the regulatory relationship between CCR5 and YAP1 was observed across various BC subtypes, TNBC patients, and showed potential relevance in fifteen additional cancer types. Overall, this study introduced an easy-to-use HTS assay that streamlines the discovery of CCL5/CCR5 axis antagonists. Verteporfin was identified as a specific molecular probe of this axis with great potentials as a therapeutic agent for treating sixteen malignant diseases characterized by heightened CCR5 and YAP1 levels.

Sacituzumab govitecan in triple-negative breast cancer: from bench to bedside, and back.

Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors.

LTBP1 promotes the progression of triple negative breast cancer via activating the RhoA/ROCK signaling pathway

<p class="MsoNormal" style="text-align: justify;"><span lang="EN-US">The latent transforming growth factor-beta (TGF-β) binding protein 1 (LTBP1) has been implicated in various cellular processes, but its role in triple-negative breast cancer (TNBC) remains unclear. In this study, we investigated the impact of LTBP1 on TNBC progression and its underlying mechanisms. Analysis of online datasets revealed elevated LTBP1 mRNA expression in breast cancer tissues compared to normal adjacent tissues. Kaplan-Meier Plotter analysis indicated that high LTBP1 expression was negatively correlated with relapse-free survival (RFS), distant-metastasis free survival (DMFS), and overall survival (OS) of breast cancer patients. Additionally, LTBP1 mRNA levels were associated with chemotherapy resistance. Functional assays in TNBC cells demonstrated that LTBP1 knockdown suppressed cell proliferation, induced apoptosis, and attenuated migration and invasion. In vivo studies confirmed that LTBP1 knockdown inhibited tumor growth in a xenograft mouse model. Mechanistically, LTBP1 positively correlated with genes involved in signaling regulation and organelle organization, with significant associations to GTPase binding and the RhoA/ROCK pathway. LTBP1 knockdown reduced RhoA activity and phosphorylation of Myosin Light Chain 2 (MLC2), suggesting inhibition of the RhoA/ROCK signaling pathway. Moreover, activation of the RhoA/ROCK pathway partially rescued the effects of LTBP1 knockdown on TNBC cell proliferation, apoptosis, migration, and invasion. In conclusion, our findings suggest that LTBP1 promotes TNBC progression through activation of the RhoA/ROCK signaling pathway, highlighting its potential as a therapeutic target for TNBC.</span></p>

Proteomic Analysis Revealed the Potential Role of MAGE-D2 in the Therapeutic Targeting of Triple-Negative Breast Cancer

Among all the molecular subtypes of breast cancer, triple-negative breast cancer (TNBC) is the most aggressive one. Currently, the clinical prognosis of TNBC is poor because there is still no effective therapeutic target. Here, we carried out a combined proteomic analysis involving bioinformatic analysis of the proteome database, label-free quantitative proteomics, and immunoprecipitation (IP) coupled with mass spectrometry (MS) to explore potential therapeutic targets for TNBC. The results of bioinformatic analysis showed an overexpression of MAGE-D2 (melanoma antigen family D2) in TNBC. In vivo and in vitro experiments revealed that MAGE-D2 overexpression could promote cell proliferation and metastasis. Furthermore, label-free quantitative proteomics revealed that MAGE-D2 acted as a cancer-promoting factor by activating the PI3K–AKT pathway. Moreover, the outcomes of IP–MS and cross-linking IP–MS demonstrated that MAGE-D2 could interact with Hsp70 and prevent Hsp70 degradation, but evidence for their direct interaction is still lacking. Nevertheless, MAGE-D2 is a potential therapeutic target for TNBC, and blocking MAGE-D2 may have important therapeutic implications.

Resveratrol-derived inhibitors of the E3 ubiquitin ligase PELI1 inhibit the metastasis of triple-negative breast cancer

Triple-negative breast cancer (TNBC), as the most challenging subtype of breast cancer, exerts highly invasive ability and metastatic nature to the lymph nodes, which is correlated with poor survival rates among patients. Pellino-1 (PELI1) is an E3 ubiquitin ligase involved in tumor invasion and metastasis, and has the potential to be developed as a novel therapeutic target for TNBC. In this study, we identified a potent inhibitor of PELI1, namely compound 3d, on the basis of natural stilbene framework through medicinal chemistry approaches. This novel PELI1 inhibitor 3d showed potent binding affinity to PELI1 (Kd 8.2 μM) in fluorescence quenching assay, and markedly interrupted the interaction of PELI1 and SNAIL/SLUG confirmed by co-immunoprecipitation. Moreover, 3d exhibited potent antitumor activity in inhibiting tumor cell migration in scratch wound healing assay without affecting cell proliferation in vitro, and down-regulated the downstream EMT-effectors of PELI1 as assessed by western blotting. In the experimental lung metastasis model, 3d showed anti-TNBC metastasis efficacy without observable toxicity in vivo.

Long non-coding RNA HANR modulates the glucose metabolism of triple negative breast cancer via stabilizing hexokinase 2

Increasing evidence has demonstrated the oncogenic roles of long non-coding RNA (lncRNA) hepatocellular carcinoma (HCC)-associated long non-coding RNA (HANR) in the development of HCC and lung cancer; however, the involvement of HANR in triple-negative breast cancer (TNBC) remains largely unknown. Our results demonstrated the significant overexpression of HANR in TNBC tissues and cells. Higher HANR levels significantly correlated with the poorer phenotypes in patients with TNBC. HANR down-regulation inhibited the proliferation and cell cycle progression and increased the apoptosis of TNBC cells. Mechanistically, immunoprecipitation-mass spectrometry revealed hexokinase II (HK2) as a direct binding target of HANR. HANR binds to and stabilizes HK2 through the proteasomal pathway. Consistent with the important role of HK2 in cancer cells, HANR depletion represses the glucose absorbance and lactate secretion, thus reprogramming the metabolism of TNBC cells. An in vivo xenograft model also demonstrated that HANR promoted tumor growth and aerobic glycolysis. This study reveals the role of HANR in modulating the glycolysis in TNBC cells by regulating HK2 stability, suggesting that HANR is a potential drug target for TNBC.

TRPML1 as a potential therapeutic target for triple-negative breast cancer: a review.

Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer, and effective treatments are urgently needed owing to its poor prognosis. Surgery, radiotherapy, and chemotherapy, alone or in combination, are the leading choices for TNBC therapy. Although promising approaches and procedures have emerged, several challenges, such as off-target effects, drug resistance, and severe side effects, remain to be addressed. Recently, transient receptor potential channel mucolipin 1 (TRPML1) has attracted the attention of researchers because its expression has been implicated in numerous diseases, including cancer. TRPML1 regulates biological events and signaling pathways, including autophagic flux, exocytosis, ionic homeostasis, and lysosomal biogenesis, all contributing to tumorigenesis and cancer progression. TRPML1 also functions as a building block for cancer cell growth, mitogenic signaling, priming tissues for metastasis, and activation of transcriptional programs, processes involved in several malignant tumors. This review provides an overview of breast cancer epidemiology and diagnostic techniques and then discusses the existing therapeutics. Additionally, we elaborate on the development of, and associated challenges to, TNBC diagnostics and treatment and the feasibility of TRPML1 as a therapeutic target for TNBC.

SHC4 orchestrates β-catenin pathway-mediated metastasis in triple-negative breast cancer by promoting Src kinase autophosphorylation

Triple-negative breast cancer (TNBC) is highly aggressive and metastatic, and has the poorest prognosis among all breast cancer subtypes. Activated β-catenin is enriched in TNBC and involved in Wnt signaling-independent metastasis. However, the underlying mechanisms of β-catenin activation in TNBC remain unknown. Here, we found that SHC4 was upregulated in TNBC and high SHC4 expression was significantly correlated with poor outcomes. Overexpression of SHC4 promoted TNBC aggressiveness in vitro and facilitated TNBC metastasis in vivo. Mechanistically, SHC4 interacted with Src and maintained its autophosphorylated activation, which activated β-catenin independent of Wnt signaling, and finally upregulated the transcription and expression of its downstream genes CD44 and MMP7. Furthermore, we determined that the PxPPxPxxxPxxP sequence on CH2 domain of SHC4 was critical for SHC4-Src binding and Src kinase activation. Overall, our results revealed the mechanism of β-catenin activation independent of Wnt signaling in TNBC, which was driven by SHC4-induced Src autophosphorylation, suggesting that SHC4 might be a potential prognostic marker and therapeutic target in TNBC.

Molecular Characterization and Establishment of a Prognostic Model Based on Primary Immunodeficiency Features in Association with RNA Modifications in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Although immunotherapy is effective for some patients, most find it difficult to benefit from it. This study aims to explore the impact of specific immune pathways and their regulated molecular mechanisms in TNBC. The gene expression data of breast cancer patients were obtained from the TCGA and METABRIC databases. Gene set variation analysis (GSVA) revealed specific upregulation or abnormal expression of immunodeficiency pathways in TNBC patients. Multi-omics data showed significant differential expression of Primary Immunodeficiency Genes (PIDGs) in TNBC patients, who are prone to genomic-level variations. Consensus clustering was used in two datasets to classify patients into two distinct molecular subtypes based on PIDGs expression patterns, with each displaying different biological features and immune landscapes. To further explore the prognostic characteristics of PIDGs-regulated molecules, we constructed a four-gene prognostic PIDG score model and a nomogram using least absolute shrinkage and selection operator (LASSO) regression analysis in combination with clinicopathological parameters. The PIDG score was closely associated with the immune therapy and drug sensitivity of TNBC patients, providing potential guidance for clinical treatment. Particularly noteworthy is the close association of this scoring with RNA modifications; patients with different scores also exhibited different mutation landscapes. This study offers new insights for the clinical treatment of TNBC and for identifying novel prognostic markers and therapeutic targets in TNBC.

CD24 May Serve as an Immunotherapy Target in Triple-Negative Breast Cancer by Regulating the Expression of PD-L1.

CD24 mediates a "don't eat me" signal to escape the immune environment. However, the correlation between CD24 and PD-L1 is unclear. This study aimed to assess if CD24 can serve as a target for immunotherapy of triple-negative breast cancer (TNBC). Data on CD24 expression in breast cancer were acquired using the Oncomine and UALCAN tools. The role of CD24 expression on the prognosis of patients with TNBC was assessed using Kaplan-Meier analyses. Subsequently, STRING and TISIDB databases were used to construct protein-protein interaction networks and to explore immune-related molecules regulated by CD24. Immunofluorescence and immunohistochemistry assays were conducted to validate CD24 and PD-L1 expression and tumor infiltration lymphocyte (TIL) level. Survival analysis was also performed to explore the effect of CD24 and PD-L1 expression and TIL level in patients with TNBC. ShRNA was also used to explore the regulation role of CD24 on PD-L1 expression. CD24 expression was significantly higher in breast cancer than in normal tissues, with high expression being significantly associated with a worse prognosis. CD24 was found to be significantly regulated by chemokines, immunoinhibitors, immunostimulators and TILs. Furthermore, CD24 expression showed a significant positive correlation with PD-L1 expression and a negative correlation with TIL level. In association with PD-L1, CD24 was found to positively regulate lymphocyte costimulation, T cell costimulation, and leukocyte activation. Furthermore, CD24 and PD-L1 co-expression contributed to worse survival outcomes. In addition, CD24 expression was found to attenuate the positive effects of high-level TILs on the prognosis of patients with TNBC. CD24 can also regulate the expression of PD-L1 in TNBC cells. CD24 may attenuate the positive effects of high TIL levels on survival and may facilitate the immune escape of TNBC by regulating PD-L1 expression. Thus, it is a potential target for immunotherapy in TNBC.

Inhibiting Endothelial Cell-Mediated T Lymphocyte Apoptosis with Integrin-Targeting Peptide-Drug Conjugate Filaments for Chemoimmunotherapy of Triple-Negative Breast Cancer.

Tumor-associated endothelial cells (TECs) limit antitumor immunity via inducing apoptosis of infiltrating T lymphocytes through a Fas ligand (FasL) mediated mechanism. Herein, this work creates a peptide-drug conjugate (PDC) by linking 7-ethyl-10-hydroxycamptothecin (SN38) to hydrophilic segments with either RGDR or HKD motif at their C-terminus through a glutathione-responsive linker. The PDCs spontaneously assemble into filaments in aqueous solution. The PDC filaments containing 1% of SN38-RGDR (SN38-HKD/RGDR) effectively target triple-negative breast cancer (TNBC) cells and TECs with upregulated expression of integrin, and induce immunogenic cell death (ICD) of tumor cells and FasL downregulation of TECs. SN38-HKD/RGDR increases infiltration, activity, and viability of CD8+ T cells, and thus inhibits the growth of primary tumors and pulmonary metastasis. This study highlights the synergistic modulation of cancerous cells and TECs with integrin-targeting PDC filaments as a promising strategy for TNBC chemoimmunotherapy.

Selective inhibition of CDK9 in triple negative breast cancer

Targeted therapy for triple-negative breast cancers (TNBC) remains a clinical challenge due to tumour heterogeneity. Since TNBC have key features of transcriptionally addicted cancers, targeting transcription via regulators such as cyclin-dependent kinase 9 (CDK9) has potential as a therapeutic strategy. Herein, we preclinically tested a new selective CDK9 inhibitor (CDDD11-8) in TNBC using cell line, patient-derived organoid, and patient-derived explant models. In vitro, CDDD11-8 dose-dependently inhibited proliferation (IC50 range: 281–734 nM), induced cell cycle arrest, and increased apoptosis of cell lines, which encompassed the three major molecular subtypes of TNBC. On target inhibition of CDK9 activity was demonstrated by reduced RNAPII phosphorylation at a CDK9 target peptide and down-regulation of the MYC and MCL1 oncogenes at the mRNA and protein levels in all cell line models. Drug induced RNAPII pausing was evident at gene promoters, with strongest pausing at MYC target genes. Growth of five distinct patient-derived organoid models was dose-dependently inhibited by CDDD11-8 (IC50 range: 272–771 nM), including three derived from MYC amplified, chemo-resistant TNBC metastatic lesions. Orally administered CDDD11-8 also inhibited growth of mammary intraductal TNBC xenograft tumours with no overt toxicity in vivo (mice) or ex vivo (human breast tissues). In conclusion, our studies indicate that CDK9 is a viable therapeutic target in TNBC and that CDDD11-8, a novel selective CDK9 inhibitor, has efficacy in TNBC without apparent toxicity to normal tissues.

Green Synthesis and Characterization of Silver Nanoparticles from Eclipta alba and Its Activity Against Triple-Negative Breast Cancer Cell Line (MDA-MB-231).

Triple-negative breast cancer (TNBC) doesn't have well-defined molecular targets making it unable to treat with chemotherapy also have faster metastatic rate and worse survival rate. In the current study we aim to target TNBC through eco-friendly green synthesized silver nanoparticles having anti-cancer phytoconstituents from the traditional anti-cancer medicinal plant Eclipta alba. Green synthesized silver nanoparticles (AgNPs) are agglomerates of spherical shaped 40-60nm sized showing characteristic light absorption at 437nm, banding pattern at 1479, 1285, 1036, and 471 showing and further X-ray diffraction pattern confirm face-centered cubic crystal silver structure exist in the green synthesized silver nanoparticle preparation. Further in vitro anti-oxidant analysis results revealed that green synthesized AgNPs showed 2.6-fold higher anti-oxidant potential (IC50 15.70g/ml) than that of aqueous plant leaf extract (IC50 39.80g/ml). In MTT cytotoxicity analysis Eclipta alba plant extract and AgNPs both display dose-dependent cytotoxicity against triple-negative breast cancer cells (MDA-MB-231), although their IC50 values differ substantially, at 105.80µg/ml and 77.20g/ml, respectively. Finally, AgNPs from Eclipta alba tested for anti-leishmanial activity and it showed 91.36 ± 1.05 for promastigotes and 76.62 ± 0.95 for amastigotes at the highest dose of 400g/ml. Altogether present data showed that Eclipta alba leaf extract actively bonded with silver nanoparticles suppresses the MDA-MB-231 cells growth through high antioxidant characters and anti-leishmanial activity. From together we confirm that Eclipta alba was recommended to a future therapeutic drug and agent to control breast cancer in the clinical level.

TNFRSF19 promotes endoplasmic reticulum stress-induced paraptosis via the activation of the MAPK pathway in triple-negative breast cancer cells.

TNFRSF19 is a member of the tumor necrosis factor receptor superfamily, and its function exhibits variability among different types of cancers. The influence of TNFRSF19 on triple-negative breast cancer (TNBC) has yet to be definitively established. In this study, bioinformatics analyses revealed that lower TNFRSF19 was associated with the poorer prognosis, higher lymph node metastasis and lower immune infiltration. Subsequently, data obtained from the TCGA database and collection of tissue samples revealed that the mRNA and protein expression levels of TNFRSF19 were observed to be significantly reduced in TNBC tissue compared to normal tissue. Additionally, the results of in vitro experiments have demonstrated that TNFRSF19 possessed the ability to inhibit the proliferation, migration and invasive capabilities of TNBC cells. In vivo trials elucidated that TNFRSF19 could suppress tumor xenografts growth. Mechanistically, TNFRSF19 initiated caspase-independent cell death and induced paraptosis. Moreover, rescue assays demonstrated that TNFRSF19 induced-paraptosis was facilitated by MAPK pathway-mediated endoplasmic reticulum (ER) stress. In conclusion, our findings demonstrated that the upregulation of TNFRSF19 functioned as a tumor suppressor in TNBC by stimulating paraptosis through the activation of the MAPK pathway-mediated ER stress, highlighting its potential to be a new therapeutic target for TNBC.

Stemness signature and targeted therapeutic drugs identification for Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and carries the worst prognosis, characterized by the lack of progesterone, estrogen, and HER2 gene expression. This study aimed to analyze cancer stemness-related gene signature to determine patients’ risk stratification and prognosis feature with TNBC. Here one-class logistic regression (OCLR) algorithm was applied to compute the stemness index of TNBC patients. Cox and LASSO regression analysis was performed on stemness-index related genes to establish 16 genes-based prognostic signature, and their predictive performance was verified in TCGA and METABERIC merged data cohort. We diagnosed the expression level of prognostic genes signature in the tumor immune microenvironment, analyzed the TNBC scRNA-seq GSE176078 dataset, and further validated the expression level of prognostic genes using the HPA database. Finally, the small molecular compounds targeted at the anti-tumor effect of predictive genes were screened by molecular docking; this novel stemness-based prognostic genes signature study could facilitate the prognosis of patients with TNBC and thus provide a feasible therapeutic target for TNBC.