Treatment Of Triple-negative Breast Cancer Research Articles

Fabrication and characterization of teriflunomide-loaded chondroitin sulfate hybridized zein nanoparticles for the management of triple negative breast cancer.

The objective of this work was to explore the Teriflunomide (TFM) -loaded chondroitin sulfate hybridized zein nanoparticles (TZCNPs) for the treatment of triple-negative breast cancer (TNBC). The particle size, PDI and %EE of optimized TZCNPs was found 208.7 ± 7.26 nm,0.173 ± 0.004, and 80.18 ± 1.03 %, respectively. TZCNPs demonstrate a 7-10 folds increase in cytotoxicity against free TFM in MDA-MB-231 cells and a 4-6 folds increase in MCF-7 cells, respectively. CD44 receptor blocking resulted in a 3.4-fold reduction in anti-cancer efficacy and a 1.7-fold decrease in cellular uptake of TZCNPs in MDA-MB-231 cells, significantly/strongly indicating the critical role of the CD44-mediated uptake mechanism. TZCNPs displayed enhanced apoptosis, mitochondrial depolarization, ROS generation, cell invasion inhibition, and inhibited colony formation compared to free TFM in MDA-MB-231 cells. TZCNPs exhibited approximately 6.8-fold enhanced cytotoxicity and a 1.66-fold decrease in spheroid volume in a multicellular tumor spheroid model of MDA-MB-231 cells compared to free TFM. TZCNPs also exhibited greater disintegration of spheroids and more dead cells (live/dead staining). In pharmacokinetic studies, TZCNPs displayed reduced CL and enhanced the AUC, MRT, and t ½ by 3.64-fold, 2.17-fold, 1.83-fold, and 1.73-fold than the free TFM suspension. An acute toxicity study revealed a good safety profile of TZCNPs, which could be a potential treatment option for TNBC.

Deep Learning and Radiomics in Triple-Negative Breast Cancer: Predicting Long-Term Prognosis and Clinical Outcomes.

Triple-negative breast cancer (TNBC) is a unique breast cancer subtype characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression in tumor cells. TNBC represents about 15% to 20% of all breast cancers and is aggressive and highly malignant. Currently, TNBC diagnosis primarily depends on pathological examination, while treatment efficacy is assessed through imaging, biomarker detection, pathological evaluation, and clinical symptom improvement. Among these, biomarker detection and pathological assessments are invasive, time-intensive procedures that may be difficult for patients with severe comorbidities and high complication risks. Thus, there is an urgent need for new, supportive tools in TNBC diagnosis and treatment. Deep learning and radiomics techniques represent advanced machine learning methodologies and are also emerging outcomes in the medical-engineering field in recent years. They are extensions of conventional imaging diagnostic methods and have demonstrated tremendous potential in image segmentation, reconstruction, recognition, and classification. These techniques hold certain application prospects for the diagnosis of TNBC, assessment of treatment response, and long-term prognosis prediction. This article reviews recent progress in the application of deep learning, ultrasound, MRI, and radiomics for TNBC diagnosis and treatment, based on research from both domestic and international scholars.

CDKN3 as a key regulator of G2M phase in triple-negative breast cancer: Insights from multi-transcriptomic analysis.

Triple-negative breast cancer (TNBC) remains a significant global health challenge, emphasizing the need for precise identification of patients with specific therapeutic targets and those at high risk of metastasis. This study aimed to identify novel therapeutic targets for personalized treatment of TNBC patients by elucidating their roles in cell cycle regulation. Using weighted gene co-expression network analysis (WGCNA), we identified 83 hub genes by integrating gene expression profiles with clinical pathological grades. A machine learning-based integrative approach further pinpointed 12 prognostic genes, among which CDKN3 exhibited the highest hazard ratio and the most adverse impact on overall survival (OS) in BC patients. Additionally, CDKN3 was identified as an independent prognostic factor for OS prediction. CDKN3 overexpression was confirmed in BC patients and validated at both mRNA and protein levels in BC cells. Knockdown of CDKN3 significantly inhibited the migration and proliferation of BC cells. Cell cycle pathway analysis revealed significant enrichment in G2M-associated pathways in BC patients, with multi-transcriptomic data indicating a close association between enhanced G2M cell cycle activity and CDKN3 upregulation in basal cancer subtypes. Pseudotime analysis further suggested CDKN3 upregulation during the G2M phase at the terminal trajectory of basal cancer subtypes, implying that CDKN3 may drive BC cell progression by promoting G2M cell cycle activity. Mechanistically, CDKN3 knockdown induced G2M cell cycle arrest in TNBC cells by downregulating CCNB2. In conclusion, CDKN3 knockdown effectively inhibits TNBC by arresting the G2M cell cycle, underscoring CDKN3 as a promising therapeutic target in TNBC treatment.

Hypomethylating agents as emerging therapeutics for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is recognized as the most aggressive subtype of breast cancer. Epigenetic silencing, such as DNA methylation mediated by DNA methyltransferases (DNMTs) plays key roles in TNBC tumorigenesis. Hypomethylating agents (HMAs) such as azacitidine, decitabine, and guadecitabine are key inhibitors of DNMTs, and accumulating evidence has shown their immunogenicity properties. In this review, the efficacy and anti-tumor immune responses triggered by HMAs in TNBC are presented and discussed. Essentially, overexpression of DNMTs is associated with poor prognosis and reduced TNBC survival rates, and these effects are negated by HMAs. In particular, HMAs could reverse epigenetic silencing of tumor suppressor genes and enhance immune recognition of TNBC cells. Clinical trials of HMAs in TNBCs are limited but early-stage trials indicate that HMAs are safe and tolerable. More clinical studies are required to establish the effectiveness of HMAs against the disease, as supported by preclinical data substantiating their effectiveness especially guadecitabine. Future research should focus on optimizing dosing and exploring combinations with immunotherapies to maximize the potential of HMAs in TNBC treatment.

Advances in antibody-drug conjugates in the treatment of advanced triple-negative breast cancer: a narrative review

Advances in antibody-drug conjugates in the treatment of advanced triple-negative breast cancer: a narrative review

Facile integration of a binary nano-prodrug with αPD-L1 as a translatable technology for potent immunotherapy of TNBC.

Immune checkpoint blockers (ICBs)-based immunotherapy is a favorable approach for efficient triple-negative breast cancer (TNBC) treatment. However, the therapeutic efficacy of ICBs is greatly compromised by immunosuppressive tumor microenvironments (TMEs) and low expression levels of programmed cell death ligand-1 (PD-L1). Herein, we constructed an amphiphilic prodrug by linking a hydrophobic STING agonist, MSA-2 and a hydrophilic chemotherapeutic drug, gemcitabine (GEM) via an ester bond, which can self-assemble into GEM-MSA-2 (G-M) nanoparticles (NPs) with a tumor growth inhibition (TGI) value of 87.1% in a murine 4T1 transplantation tumor model. Notably, the immunogenic cell death (ICD)-triggering effect of GEM together with the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation properties of MSA-2 enables efficient infiltration of non-exhausting T cells and repolarization of macrophages from M2 to M1 types in the tumor microenvironment for transforming a cold tumor to a hot one. Most importantly, G-M NPs treatment increases the PD-L1 expression levels, thus providing a unique opportunity for further integration with anti-PD-L1 monoclonal antibody (αPD-L1) for eliciting stronger immunity that ultimately leads to a TGI value of 98.0% in the primary tumor and significantly protects against distal and disseminated tumor rechallenge. Overall, this study presents a minimalist nano-prodrug combined with αPD-L1 as a simple yet robust translatable nanotechnology for potent chemo-immunotherapy of TNBC. STATEMENT OF SIGNIFICANCE: Enhancing the therapeutic efficacy of αPD-L1 for tumor immunotherapy via a translatable technology remains a challenge. We report herein facile integration of a binary nano-prodrug with αPD-L1 for potent immunotherapy of TNBC. An amphiphilic prodrug is constructed by linking a hydrophobic STING agonist, MSA-2 and a hydrophilic chemotherapeutic drug, gemcitabine (GEM) via an ester bond. The resulting self-assembled GEM-MSA-2 (G-M) nanoparticles (NPs) show a tumor growth inhibition (TGI) value of 87.1% in a murine 4T1 transplantation tumor model. Besides the induced immunogenic cell death (ICD) and activated cGAS-STING pathway, G-M NPs increase the PD-L1 expression levels, providing a unique opportunity for further integration with αPD-L1 to elicit stronger immunity that ultimately leads to a TGI value of 98.0% in the primary tumor and significantly protects against distal and disseminated tumor rechallenge.

Effectiveness of Adjuvant Capecitabine in Triple-Negative Breast Cancer Patients With Residual Disease After Neoadjuvant Treatment: A Real-World Evidence Study in Korea.

Residual disease after neoadjuvant chemotherapy (NAC) has important role in triple negative breast cancer (TNBC). The CREATE-X study demonstrated a survival benefit from adjuvant capecitabine (adjC) in breast cancer patients, especially for TNBC populations. Because the landscape of early TNBC treatment has been changing rapidly, an optimal adjuvant strategy for real-world practice is needed. We evaluated the effectiveness of adjC in TNBC patients with residual disease after NAC. We used de-identified, anonymous data from an institutional clinical data warehouse to retrospectively analyze 934 TNBC patients who received NAC between 2017 and 2023. Among them, 405 patients received at least 1 cycle of adjC, and 77 received no adjuvant treatment. The primary outcomes of the study were distant-disease free survival (DDFS) rate and overall survival (OS) rate at 3 years. The secondary outcomes were subgroup analyses and Cox regression analyses of survival outcomes. The median follow up period was 34.3 months (range 1.8-71.5). The DDFS rate at 3 years was higher in the capecitabine group: 86.3% of the capecitabine group and 74.4% of the no adjuvant group (P = .019). The OS rates at 3 years were 93.3% and 83.8%, respectively (P = .032). Subgroup analyses indicated a greater benefit from adjC in patients aged 50 years or older and those who received platinum-based NAC, both in terms of DDFS and OS. Our study showed that adjC was more effective than no adjuvant treatment for TNBC patients with residual disease in terms of DDFS and OS.

A responsive cocktail nano-strategy breaking the immune excluded state enhances immunotherapy for triple negative breast cancer.

The exclusion of immune cells from the tumor can limit the effectiveness of immunotherapy in triple negative breast cancer (TNBC). The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a crucial role in priming adaptive anti-tumor immunity through the production of type I interferons (IFNs), facilitating the maturation of dendritic cells (DCs) and the function of T cells. Although the increased expression of programmed death-ligand 1 (PD-L1) upon STING activation is favorable for amplifying the efficacy of immune checkpoint inhibitors (ICIs) and realizing combination therapy, the penetration barrier remains a major obstacle. Herein, we fabricated a smart-responsive nanosystem (B&V@ZB-MCL) by integrating the extracellular matrix (ECM)-degrading drug losartan with a STING agonist (Vadimezan, abbreviated to Vad) and a PD-L1 inhibitor (BMS-1). Losartan was first released in the acidic tumor microenvironment to overcome the physical barrier, enhancing the penetration of immunotherapeutic components. Under the triggering of 1O2 generated by a photosensitizer (Ce6), the reactive oxygen species (ROS)-sensitive degradation of the nanocore ensured the site-directed release of Vad and BMS-1. The released Vad and damaged tumor DNA activated immune responses through the cGAS-STING pathway, while the elevated expression level of PD-L1 promoted the anti-tumor effect of BMS-1. Significant degradation of collagen fibers, restoration of immune effector cells, and lower tumor volume were observed in this integrated triple drug sequential therapy, which provides a promising prospect for TNBC treatment.

Metformin-encapsulating immunoliposomes conjugated with anti-TROP 2 antibody fragments for the active targeting of triple-negative breast cancer.

Trophoblast cell-surface antigen 2 (TROP 2) has re-emerged as a promising biomarker in triple-negative breast cancer (TNBC), with high overexpression in many TNBC cases. However, despite its potential and approval as an antibody-drug-conjugate for TNBC treatment, TROP 2-targeted delivery systems are currently underexplored. Therefore, this study was aimed at exploiting the potential of TROP 2 targeting by encapsulating metformin (Met), an antidiabetic drug associated with tumor growth inhibitory properties, inside liposomes decorated with TROP 2-targeting single-chain variable fragments (scFvs). The optimization of scFv grafting resulted in Met-immunoliposomes with an average diameter of less than 200 nm, low polydispersity index (∼0.1), negative surface charge (<-10 mV), high Met drug loading (>150 mg g-1), and high affinity towards TROP 2 binding. Furthermore, Met-immunoliposomes were reproducible, and the scFv conjugation was stable in the presence of serum for five days. Their cellular uptake increased 4 folds in two-dimensional and 9 folds in three-dimensional TNBC models owing to the high affinity towards TROP 2 binding. Finally, it was observed that the therapeutic effect of Met in suppressing cancer cell growth and proliferation was superior when using anti-TROP 2 scFv-grafted Met-immunoliposomes, which completely stopped the spheroid growth and inhibited the expression of adenosine triphosphate. This study is one of the first reports to explore the combination of nanoparticle-based drug delivery systems to target the TROP 2 protein in TNBC, and to the best of our knowledge, this is the first report to specifically combine the use of scFvs with TROP 2 targeting to deliver therapeutics for TNBC treatment.

Soluble TREM2 drives triple-negative breast cancer progression via activation of the AKT pathway.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a key role in immune regulation, particularly within tumor-associated macrophages (TAMs). In triple-negative breast cancer (TNBC), TREM2+ TAMs have been shown to modulate the tumor microenvironment, but the role of its soluble form: soluble triggering receptor expressed on myeloid cells 2 (sTREM2), produced through proteolytic cleavage, remains unclear. In this study, we investigated the effects of sTREM2 on TNBC progression. In vitro, treatment of TNBC cells with recombinant sTREM2 or sTREM2-containing culture supernatant significantly enhanced cell proliferation, invasion, and migration. These effects were further confirmed by the use of TREM2-neutralizing antibodies, which abrogated sTREM2's tumor-promoting activities. In vivo, peri-tumoral injections of recombinant sTREM2 led to a notable acceleration of tumor growth in mouse models. Mechanistically, we found that the effects of sTREM2 were mediated through its binding to the TG2 protein in 4T1 cells, thereby activating the AKT signaling pathway. Collectively, our findings suggest that sTREM2 drives TNBC progression by enhancing critical tumor cell functions, positioning it as a potential therapeutic target for TNBC treatment.

Integrating Deep Learning with Biology: A New Frontier in Triple-Negative Breast Cancer Treatment Prediction?

Integrating Deep Learning with Biology: A New Frontier in Triple-Negative Breast Cancer Treatment Prediction?

A novel lncRNA AC112721.1 promotes the progression of triple-negative breast cancer by directly binding to THBS1 and regulating miR-491-5p/C2CD2L axis

Triple-negative breast cancer (TNBC) seriously threatens women’s health, and long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in TNBC. This study aimed to identify lncRNAs that represent effective targets for the early diagnosis or treatment of TNBC. Here, we utilized the TCGA database to analyze differentially expressed genes, and survival analysis and ROC curve analysis were also performed. Notably, we identified a novel lncRNA, AC112721.1, that is significantly overexpressed in TNBC and is associated with poor overall survival in TNBC patients. Loss- and gain-of-function experiments revealed that AC112721.1 significantly promoted cell proliferation and migration, suppressed cell apoptosis in vitro and inhibited tumorigenesis in vivo. Further study of the mechanisms underlying these effects revealed that AC112721.1 regulates the Ras pathway by directly binding to THBS1 protein and functions as a ceRNA by sponging miR-491-5p to increase the expression of C2CD2L, thereby influencing the progression of TNBC. Our findings indicate that AC112721.1 may represent a new biomarker for evaluating TNBC prognosis and treating TNBC.

Self-propelling, protein-bound magnetic nanobots for efficient in vitro drug delivery in triple negative breast cancer cells

The emergence of self-propelling magnetic nanobots represents a significant advancement in the field of drug delivery. These magneto-nanobots offer precise control over drug targeting and possess the capability to navigate deep into tumor tissues, thereby addressing multiple challenges associated with conventional cancer therapies. Here, Fe-GSH-Protein-Dox, a novel self-propelling magnetic nanobot conjugated with a biocompatible protein surface and loaded with doxorubicin for the treatment of triple-negative breast cancer (TNBC), is reported. The self-propulsion of magnetic nanobots occurs due to a catalytic interaction between Fe3O4 nanoparticles and hydrogen peroxide. This interaction results in generation of O2 bubbles and high-speed propulsion in blood serum. Cell entry kinetic studies confirmed higher internalization of the drug into TNBC cells with Fe-GSH-Protein-Dox nanobots, resulting in a lower observed IC50 and higher potential to kill cancer cells compared to free doxorubicin. Moreover, fluorescence imaging studies confirmed an increase in the production of reactive oxygen species, leading to maximum cellular damage. Endocytosis studies elucidate the mechanism of cellular internalization, revealing clathrin-mediated endocytosis, while the cell cycle study demonstrates significant cell cycle arrest in the G2-M phase. Thus, the designed protein-conjugated self-propelling magnetic nanobots have the potential to develop into a novel drug delivery platform for clinical applications.

Spatiotemporal-controllable ROS-responsive camptothecin nano-bomb for chemo/photo/immunotherapy in triple-negative breast cancer

Chemotherapy is still one of the major approaches in triple-negative breast cancer (TNBC) treatment. The development of new formulations for classic chemotherapeutic drugs remains interests in studies. Camptothecin (CPT) is powerful antitumor agents in TNBC treatment though its clinic applications are limited by its low water solubility and systemic toxicity. To prepare a spatiotemporal controllable CPT nano-formulation, we construct a ROS-responsive self-assembly nanoparticle by combining hydrophobic CPT and hydrophilic 5-floxuridine (FUDR). A ROS-sensitive thioketal (TK) linker is used to prepare CPT-TK-FUDR (CTF). Next, we introduced IR780-based phototherapy to elicit massive ROS regeneration due to the endogenous ROS is not sufficient. IR780 is modified with hyaluronic acid (HA) to prepare HA-modified IR780 (HAIR) for its biocompatibility and tumor targeting ability improvement. CTF and HAIR self-assemble to form an attractive nano-bomb (HAIR/CTF NPs). HA accurately guides the NPs to tumor sites via HA-receptor recognition on tumor cells. After internalization, overexpressed intracellular HAase in tumor cells disassembles the NPs to free the contents. Due to the presence of IR780 molecules, the scheduled irradiation of 808 nm laser induces massive reactive oxygen species (ROS) generation, which further result in the cleavage of TK linker for free drugs release. Additionally, ROS-mediated photodynamic therapy (PDT) and near-infrared laser-mediated photothermal therapy (PTT) synergistically worked to eradicate tumor cells. Then immunogenic cell death (ICD) was evoked by CPT and phototherapy to amplify antitumor immunity, thereby achieving primary and abscopal tumor inhibition. In conclusion, the HAIR/CTF nano-bomb realized spatiotemporal controllable drug release, exciting tumor eradication and attractive anti-metastasis efficacy via combination chemo/photo/immunotherapy, offering a valuable reference for the re-development of classic drug in future clinical practice.Graphical

Microtubule-Targeting NAP Peptide-Ru(II)-polypyridyl Conjugate As a Bimodal Therapeutic Agent for Triple Negative Breast Carcinoma.

Triple-negative breast cancer (TNBC) poses significant treatment challenges due to its high metastasis, heterogeneity, and poor biomarker expression. The N-terminus of an octapeptide NAPVSIPQ (NAP) was covalently coupled to a carboxylic acid derivative of Ru(2,2'-bipy)32+ (Rubpy) to synthesize an N-stapled short peptide-Rubpy conjugate (Ru-NAP). This photosensitizer (PS) was utilized to treat TNBC through microtubule (MT) targeted chemotherapy and photodynamic therapy (PDT). Ru-NAP formed more elaborate molecular aggregates with fibrillar morphology as compared to NAP. A much higher binding affinity of Ru-NAP over NAP toward β-tubulin (KRu-NAP: (6.8 ± 0.55) × 106 M-1; KNAP: (8.2 ± 1.1) × 104 M-1) was observed due to stronger electrostatic interactions between the MT with an average linear charge density of ∼85 e/nm and the cationic Rubpy part of Ru-NAP. This was also supported by docking, simulation, and appropriate imaging studies. Ru-NAP promoted serum stability, specific binding of NAP to the E-site of the βIII-tubulin followed by the disruption of the MT network, and effective singlet oxygen generation in TNBC cells (MDA-MB-231), causing cell cycle arrest in the G2/M phase and triggering apoptosis. Remarkably, MDA-MB-231 cells were more sensitive to Ru-NAP compared to noncancerous human embryonic kidney (HEK293 cells) when exposed to light (LightIC50Ru-NAP[HEK293]: 17.2 ± 2.5 μM, compared to LightIC50Ru-NAP[MDA-MB-231]: 32.5 ± 7.8 nM, DarkIC50Ru-NAP[HEK293]: > 80 μM, compared to DarkIC50Ru-NAP[MDA-MB-231]: 2.9 ± 0.5 μM). Ru-NAP also effectively inhibited tumor growth in MDA-MB-231 xenograft models in nude mice. Our findings provide strong evidence that Ru-NAP has a potential therapeutic role in TNBC treatment.

Concurrent Amplification of Ferroptosis and Immune System Activation Via Nanomedicine-Mediated Radiosensitization for Triple-Negative Breast Cancer Therapy.

Radiation therapy (RT) is one of the core therapies for current cancer management. However, the emergence of radioresistance has become a major cause of radiotherapy failure and disease progression. Therefore, overcoming radioresistance to achieve highly effective treatment for refractory tumors is significant yet challenging. Here, pH-responsive DSPE-PEoz modified hollow Bi2Se3-RSL3/diABZi (DP-HBN/RA) nanomedicine is designed as a radiation sensitizer for efficient treatment of triple-negative breast cancer by simultaneously amplifying ferroptosis and immune system activation. DP-HBN/RA can efficiently concentrate X-ray radiation energy inside the tumor, thereby promoting precise ionizing radiation exposure in tumor cells to produce large amounts of reactive oxygen species (ROS), leading to lipid peroxidation-induced ferroptosis. Meanwhile, ferroptotic cell death is intensified through the inactivation of GPX4 by RSL3 released from DP-HBN/RA to acidic conditions in the tumor microenvironment. Additionally, DP-HBN/RA enhances RT efficacy to exacerbate unrepairable DNA damage and release DNA fragments that activate the cGAS-STING signal pathway, evoking a systematic immune response. Ingeniously, the released diABZi reinforces cGAS-STING activation to boost the immunology antitumor effect. This work links the induction of ferroptosis and the initiation of systematic immune response to achieve highly effective tumor suppression, which opens up new avenues for future treatments of refractory tumors.

CBL0137 and NKG2A blockade: a novel immuno-oncology combination therapy for Myc-overexpressing triple-negative breast cancers.

The MYC proto-oncogene is upregulated in >60% of triple-negative breast cancers (TNBCs), it can directly promote tumor cell proliferation, and its overexpression negatively regulates anti-tumor immune responses. For all these reasons, MYC has long been considered as a compelling therapeutic target. However, pharmacological inhibition of MYC function has proven difficult due to a lack of a drug-binding pocket. Here, we demonstrate that the potent abrogation of MYC gene transcription by CBL0137 induces immunogenic cell death and reduces proliferation in MYC-high but not in MYC-low TNBC in vitro. CBL0137 also significantly inhibited the in vivo growth of primary tumors in a human MYC-high TNBC xenograft model (MDA-MB-231). Moreover, CBL0137 inhibited the tumor growth of highly aggressive mouse 4T1.2 syngeneic TNBC model in immunocompetent mice by inhibiting the MYC pathway and inducing Type I interferon responses. Immune profiling of CBL0137-treated mice revealed significantly enhanced tumor-specific immune responses and increased proportions of tumor infiltrating effector CD8+ T cells, CD4+ T cells, and NK cells. CBL0137-induced immune activation also resulted in increased exhaustion of immune effector cells. In particular, NKG2A up-regulation on activated effector cells and of its ligand Qa-1b on tumors in vivo was identified as a possible immune evasive mechanism. Indeed, NKG2A blockade synergized with CBL0137 significantly inhibiting the in vivo growth of 4T1.2 tumors. Collectively, our findings provide the rationale supporting the exploitation of CBL0137-induced anti-tumor immunity in combination with NKG2A blockade to improve the treatment of TNBC expressing high levels of MYC.

Use of Gain-of-Function Screening to Identify miRNAs Involved in Paclitaxel Resistance in Triple-Negative Breast Cancer.

Paclitaxel is a widely used chemotherapeutic agent for the treatment of breast cancer (BC), including as a front-line treatment for triple-negative breast cancer (TNBC) patients. However, resistance to paclitaxel remains one of the major causes of death associated with treatment failure. Multiple studies have demonstrated that miRNAs play a role in paclitaxel resistance and are associated with both disease progression and metastasis. In the present study, we used a miRNA-encoding lentiviral library as a gain-of-function screen for paclitaxel resistance in the MDA-MB-231 TNBC cell line. We identified that miR-181b, miR-29a, miR-30c, miR-196 and miR-1295 conferred a resistant phenotype to cells. The expression of miR-29a also induced resistance to eribulin and vinorelbine, while miR-181b and miR-30c induced resistance to vinorelbine. We measured the levels of these miRNAs in breast cancer patients and observed higher levels of miR-29a in treatment-refractory patients. Taken together, we suggest that miR-29a and miR-181b may be good candidates for miRNA inhibition to overcome resistance to chemotherapy.

Pentagalloyl Glucose from Bouea macrophylla Suppresses the Epithelial-Mesenchymal Transition and Synergizes the Doxorubicin-Induced Anticancer and Anti-Migration Effects in Triple-Negative Breast Cancer.

Background: Triple-negative breast cancer (TNBC) represents an aggressive form of breast cancer with few available therapeutic options. Chemotherapy, particularly with drugs like doxorubicin (DOX), remains the cornerstone of treatment for this challenging subtype. However, the clinical utility of DOX is hampered by adverse effects that escalate with higher doses and drug resistance, underscoring the need for alternative therapies. This study explored the efficacy of pentagalloyl glucose (PGG), a natural polyphenol derived from Bouea macrophylla, in enhancing DOX's anticancer effects and suppressing the epithelial-mesenchymal transition (EMT) in TNBC cells. Methods: This study employed diverse methodologies to assess the effects of PGG and DOX on TNBC cells. MDA-MB231 triple-negative breast cancer cells were used to evaluate cell viability, migration, invasion, apoptosis, mitochondrial membrane potential, and protein expression through techniques including MTT assays, wound healing assays, flow cytometry, Western blotting, and immunofluorescence. Results: Our findings demonstrate that PGG combined with DOX significantly inhibits TNBC cell proliferation, migration, and invasion. PGG enhances DOX-induced apoptosis by disrupting the mitochondrial membrane potential and activating caspase pathways; consequently, the activation of caspase-3 and the cleavage of PARP are increased. Additionally, the study shows that the combination treatment upregulates ERK signaling, further promoting apoptosis. Moreover, PGG reverses DOX-induced EMT by downregulating mesenchymal markers (vimentin and β-catenin) and upregulating epithelial markers (E-cadherin). Furthermore, it effectively inhibits STAT3 phosphorylation, associated with cell survival and migration. Conclusions: These results highlight the potential of PGG as an adjuvant therapy in TNBC treatment. PGG synergizes with DOX, which potentiates its anticancer effects while mitigating adverse reactions.

Hyaluronic acid-functionalized supramolecular nanophotosensitizers for targeted photoimmunotherapy of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is recognized as a particularly aggressive subtype of breast cancer that is devoid of effective therapeutic targets. Immune checkpoint inhibitors (ICIs) have demonstrated promising results in TNBC treatment. Nonetheless, most patients either develop resistance to ICIs or fail to respond to them initially. Owing to its spatio-temporal precision and non-invasive nature, photoimmunotherapy offers a targeted therapeutic strategy for TNBC. Herein, we report hyaluronic acid (HA)-functionalized indocyanine green-based supramolecular nanoparticles (HGI NPs), with biodegradable characteristics, for high-performance photoacoustic imaging and targeted phototherapy for TNBC. Notably, HGI NPs can significantly gather in TNBC tissues because of the enhanced permeability and retention effect of the tumor, and the tumor-targeting properties of HA. The strong amplification of HGI nanoparticles triggers a significant immunogenic cell death (ICD) response when exposed to 808 nm light, thus shifting the immunosuppressive tumor microenvironment (iTME) into a tumor attack mode and ‘hot’ state. Antitumor experiments demonstrate the high efficiency of the supramolecular photosensitizers HGI NPs for TNBC elimination and good biosafety. This synergistic strategy reshapes the iTME and amplifies the antitumor immune response, providing a theoretical foundation for combining phototherapy and ICIs as potential treatments for TNBC.Graphical