Search Results (3,145)

Background/Objectives: There is a clear need for more options to control the progression of breast cancer and prevent the occurrence of breast cancer in minority populations that have a higher rate of mortality due to triple-negative breast cancer (TNBC) subtypes. Prevalent nutraceuticals such as Ashwagandha (also known as the Indian Winter Cherry) have anti-inflammatory and apoptotic capabilities, as well as the ability to inhibit cancer growth. The purpose of this study is to analyze the novel combination of withaferin A (derived from the Indian Winter Cherry and known to have histone deacetylase inhibition capabilities) and sodium butyrate (a short-chain fatty acid produced from the gut microbiome and known to have DNA methyltransferase inhibition capabilities) treatment on breast cancer-derived cell lines. There is a scientific gap of possible causality of decreasing breast cancer progression when treated with sodium butyrate and withaferin A. Methods: Two in vitro cell viability assays were utilized consisting of [MTT (4,5 Dimethylthiazol-2-yl)] and the neutral red assay to analyze the impact of treatment of compounds alone and in combination on breast cancer cells for 72 h. The Highest Single Agent (HSA) combination analysis was utilized to derive combination indexes for our breast cancer cell types. Protein and gene expression was investigated for Class 1 histone deacetylases, de novo DNA methyltransferase, the p65 subunit of NF-κB, and NFκB1. Lastly, DNA methyltransferase enzymatic activity was analyzed via the Epigentek DNMT Activity/Inhibition ELISA Easy Kit. Results: Through the cell viability assay [MTT (4,5 Dimethylthiazol-2-yl)], MCF−7, MDA−MB−231, and MDA−MB−157 cells were found to have a decrease in cell viability due to combinatorial treatment with withaferin A and sodium butyrate. Western blot results depicted a decrease in protein expression levels for DNA methyltransferases due to the administration of 2.5 mM sodium butyrate and 0.2 µM withaferin A alone and in combination for breast cancer cell lines MCF−7, MDA-MB-231, and MDA−MB−157. Additionally, the combination of these two components have successfully inhibited the progression of the NFκB1 gene within analysis through the quantitative polymerase chain reaction (qPCR). Conclusions: The novel combination of withaferin A and sodium butyrate have markedly reduced the progression of breast cancer-derived cell lines for cell viability, epigenetic DNMT gene expression, as well as inhibiting NFκB1 signaling on the gene expression level. Full article

Background/Objectives: The role of pre-treatment breast magnetic resonance imaging (MRI) findings and apparent diffusion coefficient (ADC) values in predicting pathologic complete response (pCR) in breast cancer patients receiving neoadjuvant chemotherapy (NAC) has not yet been sufficiently clarified, especially in the context of molecular subtype differences. In this study, we questioned whether these imaging parameters were independent predictors of pCR. Methods: This study retrospectively explored MRI characteristics of 188 patients who underwent NAC from 2015 to 2023. The patients were divided into the pCR-positive and pCR-negative groups—the latter comprising patients with partial response (n = 61) and stable disease (n = 90)—and were classified into four molecular subtypes: Luminal A/B, HER2-enriched, and triple-negative breast cancer (TNBC). The MRI parameters included pre-chemotherapy T2-weighted signal characteristics, shape features, contrast kinetics, peritumoral edema, and ADC MIN/ADC MAX. Post-treatment ADC and ΔADC were the post-chemotherapy MRI parameters. Independent predictors were evaluated by logistic regression and discriminant performance by ROC analysis. Results: The overall pCR rate was 19.7%. In multivariate analysis, T2-weighted isointense signal (OR = 4.50), uniform tumor shape (OR = 12.83), HER2-enriched subtype (OR = 6.03), TNBC (OR = 5.15), ADC MIN (OR = 1.41), tumor size (OR = 1.28), and kinetic Type 3 pattern (OR = 3.21) were identified as independent predictors. Pre-treatment ADC MIN yielded an AUC of 0.724, while post-treatment ADC achieved 100% sensitivity and 96.7% specificity (AUC = 0.967). Conclusions: MRI morphology and ADC values may make a meaningful contribution to the prediction of pCR when evaluated in the context of molecular subtype. Post-treatment ADC demonstrated particularly strong discriminatory performance; however, external validation in multicenter cohorts is required before clinical implementation. Full article

Background and Objectives: A combination of chemotherapy and immunotherapy may improve cancer treatment outcomes; however, determining which patient groups will benefit from immunotherapy is critical. Triple-negative breast cancer (TNBC) achieves limited benefit from immune checkpoint inhibitors (ICIs) and anti-PD-L1 blockade therapy. Materials and Methods: In this study, PD-L1 expression levels in myeloid-derived cells in the tumor microenvironment were determined in an experimental TNBC model. Results: Compared with tumor cells, granulocytes, monocytes, and macrophages had significantly higher PD-L1 expression. CD206⁺ tumor-associated macrophages (TAMs) expressed the highest level of PD-L1. PD-L1 positivity in TAMs was also significantly high in the lung, liver, lymph node, and spleen. Despite treatment initiation in late-stage tumorigenesis, the combination of paclitaxel and the anti-PD-L1 monoclonal antibody atezolizumab significantly reduced tumor growth. In addition, lung metastasis burden was reduced with combined treatment compared with chemotherapy or anti-PD-L1 monotherapy alone. Conclusions: As a result, alterations in PD-L1⁺ myeloid cells and immune infiltration can be associated with atezolizumab and paclitaxel therapy success in triple-negative breast cancer. Full article

Triple-negative breast cancer (TNBC) cells with intact homologous recombination (HR) repair mechanism can survive treatment with Olaparib, which further limits the clinical application of PARP1/2 inhibitors. Previous studies have demonstrated that inhibition of indoleamine 2,3-dioxygenase (IDO) can enhance the sensitivity of human tumor cells to PARP1/2 inhibitors. However, the mechanisms underlying their synergistic effects in the treatment of TNBC remain unclear. Herein, we demonstrate that the combination of Olaparib and Epacadostat significantly reduces the proliferation of BRCA-proficient MDA-MB-231 and MDA-MB-468 cells compared to either monotherapy. Mechanistically, Epacadostat reduces intracellular kynurenine and NAD⁺ levels, thereby sensitizing TNBCs to PARP1/2 inhibition and significantly amplifying Olaparib-induced DNA damage. Furthermore, Epacadostat and Olaparib synergistically increase cellular reactive oxygen species (ROS), leading to DNA oxidative damage and apoptosis. In vivo, Epacadostat and Olaparib significantly suppressed MDA-MB-468 tumor growth compared to the monotherapy groups, while promoting an increase in phosphorylated H2AX. Notably, the dual inhibition of IDO1 and PARP1/2 specifically reduced the expression of HR core genes and proteins, such as BRCA1 and RAD51, which may contribute to impaired DNA-damage repair and increased sensitivity to Olaparib. In summary, targeting both IDO1 and PARP1/2 represents a promising combination therapy for BRCA-proficient TNBC. Full article

Background/Objectives: Patients with metastatic breast cancer and visceral crisis are systematically excluded from clinical trials, leaving clinicians without evidence-based therapeutic guidance. To the best of our knowledge, no published reports have described the use of combined chemo-immunotherapy in mTNBC complicated by hepatic visceral crisis. Case presentation: We report the case of a 45-year-old woman with PD-L1-high recurrent TNBC who presented with acute, life-threatening hepatic failure. Laboratory evaluation revealed marked transaminase elevation, cholestasis, rising bilirubin levels, and clinical deterioration consistent with hepatic visceral crisis. Due to severe hepatic impairment, a sequential therapeutic strategy was adopted: treatment was initiated with dose-reduced weekly paclitaxel (80% of the standard dose), and pembrolizumab (200 mg every three weeks) was introduced at the fourth cycle. Shortly after immunotherapy initiation, the patient experienced rapid clinical improvement accompanied by significant biochemical recovery and radiologic tumor regression. Although disease progression occurred after four months, hepatic visceral crisis did not recur. Discussion: This case questions the conventional restriction of immunotherapy in the setting of severe hepatic dysfunction. The rapid biochemical recovery observed after pembrolizumab initiation suggests that immunologic antitumor activity may be preserved despite significant hepatic impairment. Furthermore, the high PD-L1 expression in this patient indicates that its predictive value may extend even to the context of visceral crisis. Conclusions: Our findings suggest that immunotherapy in combination with chemotherapy may represent a feasible therapeutic strategy in selected patients with PD-L1-high mTNBC presenting with hepatic visceral crisis. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies and characterized by pronounced heterogeneity and widespread dysregulation of microRNAs (miRNAs) that influence epithelial-to-mesenchymal transition (EMT) and metastasis. Tumor-derived extracellular vesicles (tEVs) further contribute to TNBC progression by transporting oncogenic cargo that can enhance pro-inflammatory signaling. The synthetic SMRwt peptide has been suggested to modulate oncogenic pathways; however, its effects on EV miRNA composition and inflammatory transcript profiles in TNBC remain unclear. Here, we investigated whether SMRwt alters tEV-associated miRNAs and cytokine transcript signatures relevant to EMT and inflammasome-linked pathways. Extracellular vesicles were isolated from SMR-treated and untreated MDA-MB-231 cells, followed by nanoparticle tracking analysis and small RNA sequencing. SMRwt treatment enriched 11 tumor-suppressive miRNAs (including Let-7a-5p, Let-7b-5p, miR-24-3p, miR-26b-5p, miR-92a-3p, miR-93-5p, and miR-496) previously associated with the regulation of proliferation, EMT, migration, and metastasis. We also observed modest, non-significant decreases (1.01–1.27-fold) in oncogenic miR-1200, miR-374a-5p, and miR-937-3p, which have been implicated in the progression of breast, lung, and bone malignancies. Complementary transcriptomic profiling using the NanoString nCounter Breast Cancer 360 Gene Expression Panel (NanoString Technologies, Inc., Seattle, CA, USA) demonstrated reduced expression of inflammasome-associated cytokines in TNBC cells relative to non-tumorigenic controls, including a log₂ fold change of −1.15 for IL 1β (MDA-MB-231 vs. MCF10A). These transcript-level changes suggest potential modulation. Additionally, SMRwt suppresses ASC-mediated caspase-1 activation and reduces IL-1β secretion, thereby inhibiting NLRP3 inflammasome signaling. Therefore, we infer that SMRwt simultaneously restores tumor-suppressive miRNA networks and suppresses inflammasome-driven inflammation, supporting its potential as a dual-target therapeutic strategy for TNBC. Full article

Background/Objectives: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is linked to poorer overall survival and a higher risk of brain metastases compared to HER2-negative breast cancer. Current preclinical studies lack robust HER2+ metastatic syngeneic mouse models for investigating targeted and immunomodulatory therapies. This study aims to develop effective HER2+ mouse models to investigate response dynamics to HER2-targeted therapy and immunotherapy. Methods: The human HER2 gene (WT or mutant p.A775_G776insYVMA, GFP-tagged at the C-terminus) was introduced into triple-negative breast cancer (TNBC) mouse mammary carcinoma cells with known metastatic potential (4T1 and EO771) via lentiviral transduction. HER2 expression and phosphorylation were analyzed using Western blotting and immunohistochemistry. Tumors were treated with HER2-targeted therapy (trastuzumab and tucatinib), immune checkpoint blockade (anti-PD-1 and anti-CTLA-4), and anti-HER2 antibody–drug conjugate (ADC) to evaluate treatment efficacy. Metastatic potential was assessed with brain fluorescence imaging. Statistical analysis included ANOVA and Kaplan–Meier tests. Results: Newly established lines demonstrated expression of HER2+, with HER2^YVMA lines showing higher phosphorylation than HER2^WT lines. Cells were tumorigenic, demonstrating in vivo tumor take rates at 100% for 4T1-HER2 and 15–30% for EO771-HER2. HER2 overexpression led to a 30% increase in spontaneous brain metastasis in the 4T1-HER2 models. Trastuzumab alone did not reduce primary tumor size but significantly reduced brain GFP signal by 17% ± 8% and 26% ± 7% in the 4T1-HER2^WT and 4T1-HER2^YVMA models, respectively. Combinational therapies with anti-HER2 therapy and immune checkpoint blockade effectively suppressed primary tumor growth and prolonged survival in EO771-HER2^YVMA model. T-Dxd, but not T-DM1, demonstrated partial treatment response in the EO771-HER2^WT model. Conclusions: HER2+ syngeneic tumor models were developed that spontaneously metastasize to the brain and demonstrate variable responses to immunotherapies and ADCs. These models are valuable for advancing molecular imaging modalities for HER2+ brain metastasis, studying blood–brain barrier penetration of HER2-targeted drugs, and exploring the combination of therapies, including immunotherapy. Full article

Triple-negative breast cancer (TNBC) poses significant therapeutic challenges due to the limited availability of targeted treatment options and the development of resistance to chemotherapy, including doxorubicin (DOX). The objective of this study was to investigate the impact of inhibiting activated pathways in DOX-resistant TNBC and examine the effects on MAPK and PI3K/Akt signaling pathways, cell cycle regulation, and the regulators of the epithelial–mesenchymal transition (EMT) process. Continuous exposure of cells to increasing concentrations of DOX resulted in the selection of resistant cells that exhibited EMT characteristics. We assessed the expression levels of markers related to cell death, survival, mitophagy pathways and EMT using Western blotting and qPCR in both sensitive and resistant cells with activated-pathway inhibitor treatments. Additionally, we demonstrated differences in migration capacity between resistant and sensitive cells with or without inhibitor treatments. It was found that MEK inhibition was less effective than PI3K inhibition in both sensitive and resistant cells. Expression analyses clearly demonstrated that resistant cells exhibited more aggressive behavior, as indicated by EMT- and survival-related gene expressions. The combination of MEK and PI3K inhibitors was more effective in shutting down these signals in both cell types. The ability to induce EMT in DOX-resistant cells revealed that one form of resistance might combine with another, acting as a mediator for cellular switch. Although drug resistance and various inhibitors reduce the proliferative capacity of cells and related parameters, resistance contributes to the acquisition of metastatic characteristics. Full article

Background/Objectives: Programmed death ligand 1 (PD-L1) is often overexpressed in triple-negative breast cancer (TNBC), where it helps the tumor evade the immune system and promotes tumor growth. Interleukin-24 (IL-24) is recognized for its anti-tumor activity, although its role in immune regulation remains unclear. In this study, we examined the role of IL-24 in regulating PD-L1 and its anti-cancer activity in TNBC cells. Methods: The study used TNBC cell lines treated with IL-24, delivered via a non-replicating adenovirus vector expressing the IL-24 gene. Assays included MTT for cell viability, Annexin V for apoptosis, Western blot for protein analysis, and qRT-PCR for mRNA analysis. Results: We found that the highly aggressive MDA-MB-231 cells had significantly higher PD-L1 levels. We discovered that treatment with IL-24 reduced cell growth, induced apoptosis, and significantly decreased PD-L1 protein levels in MDA-MB-231 cells. Mechanistically, we identified PKR, also known as eukaryotic translation initiation factor 2 alpha kinase 2, as a key mediator of IL-24–induced PD-L1 suppression. Additionally, doxorubicin, a primary chemotherapy drug used to treat triple-negative breast cancer, decreases PD-L1 expression and increases the sensitivity when combined with IL-24. Conclusions: In this study, we show that IL-24 decreases PD-L1 expression in MDA-MB-231 cells through PKR activation, enhances the anti-tumor effects of Doxorubicin, and may enable lower doses that reduce toxicity and further decrease PD-L1 levels. These findings suggest that IL-24 could serve as a valuable target for therapeutic intervention and suggest that it can improve doxorubicin’s effectiveness against aggressive breast cancer. Full article

Upregulation of glutaminase enzymatic activity promotes tumour cell proliferation. Its overexpression correlates with poor disease outcome in patients, including those with breast cancer. A selective glutaminase inhibitor, CB-839, which targets cancer cells by blocking glutamine conversion to glutamate, has shown promising preclinical results as a therapeutic target in triple-negative breast cancer treatment. The current study aimed to determine the importance of glutaminase in Oestrogen Receptor positive/luminal breast cancer to potentially identify therapeutic targets to treat this subtype. In vitro studies using luminal breast cancer cells were performed to investigate the effects of siRNA knockdown of glutaminase genes (GLS and GLS2) and inhibition using CB-839 on functional assays. Silencing GLS in luminal breast cancer cells significantly reduced cell proliferation whilst inducing apoptosis. A similar impact on cell proliferation was observed when silencing GLS2 in luminal B cells, but there was no observed effect on cell apoptosis and cell cycle. There was little effect of GLS inhibition using CB-839 in luminal breast cancer. This study demonstrates that glutaminase is necessary for luminal breast cancer growth and survival. Co-targeting GLS and GLS2 might be a novel approach for the treatment of this subclass. Further functional studies to evaluate the underlying molecular mechanisms of this process are warranted. Full article

Triple-negative breast cancer (TNBC) represents 10–20% of breast cancers and is characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, leaving cytotoxic chemotherapy as the main systemic treatment. However, rapid development of resistance, via drug efflux, enhanced DNA repair, apoptosis evasion, epithelial-to-mesenchymal transition, and tumor microenvironment protection, limit long-term efficacy. Small interfering RNA (siRNA) therapeutics can silence key resistance drivers, but their clinical potential is hindered by instability, poor biodistribution, and off-target effects. Nanocarrier-based delivery systems offer solutions by protecting siRNA, enhancing tumor accumulation, enabling targeted intracellular release, and permitting co-delivery with chemotherapeutics for synergistic effects. We conducted a narrative review in PubMed from database inception to August 2025. The included studies demonstrated that lipid, polymeric, inorganic, and hybrid nanocarriers can achieve efficient target knockdown, reverse drug resistance mechanisms, and significantly enhance antitumor responses in resistant TNBC models. Several platforms also reduced metastatic spread and improved survival in vivo. While preclinical results are compelling, clinical translation remains limited by incomplete safety profiling and heterogeneity in delivery efficiency. This review synthesizes mechanistic insights and delivery innovations, outlining a roadmap for translating siRNA-loaded nanocarriers into effective therapies for chemoresistant TNBC. Full article

Triple-negative breast cancer (TNBC) remains highly aggressive and refractory to conventional treatments, underscoring the need for novel combination strategies. Here, we employed 2D and 3D in vitro models, transcriptomic profiling, and in vivo xenograft studies to evaluate the anticancer efficacy of cannabinoids combined with the terpene β-caryophyllene (BC) in resistant TNBC models. Among the tested cannabinoids, cannabichromene (CBC) exhibited the greatest potency, and its combination with BC at sub-toxic concentrations significantly reduced IC₅₀ values, enhanced cytotoxicity in spheroids, and suppressed colony formation and migration. The combination treatment induced pronounced G1 cell cycle arrest and increased apoptotic cell death. Western blot analyses revealed downregulation of PARP, Survivin, mTOR, Vimentin, Glypican-5, and PD-L1, while RNA sequencing demonstrated suppression of proliferative and migratory signaling pathways alongside activation of apoptosis, autophagy, and ferroptosis-related pathways. In vivo, CBC + BC significantly inhibited tumor growth in MDA-MB-231 xenografts, outperforming single-agent treatments. Collectively, these findings demonstrate that BC synergistically enhances cannabinoid activity, yielding superior antiproliferative and anti-migratory effects, and highlight this combination as a promising therapeutic strategy for resistant TNBC. Full article

Triple-negative breast cancer (TNBC) remains one of the most aggressive breast cancer subtypes and is associated with limited therapeutic options, underscoring the urgent need for novel treatment strategies. In this study, a library of seventeen 1,3,5-triazine derivatives potentially targeting TNBC was developed using an activity-based approach. Compounds were synthesized via an ultrasound-assisted protocol, providing an efficient and environmentally friendly methodology. The synthesized library was evaluated in vitro against the human TNBC cell lines MDA-MB-468, MDA-MB-231, and Hs578T, as well as the non-tumorigenic epithelial cell line MCF10A. Compounds 9 and 17 exhibited the most promising antiproliferative activity against TNBC cell lines (MDA-MB-468: IC₅₀ = 36.62 µM for 9 and 38.29 µM for 17; MDA-MB-231: IC₅₀ = 37.32 µM for 9 and 32.86 µM for 17; Hs578T: IC₅₀ = 57.26 µM for 9 and 34.87 µM for 17), while maintaining acceptable selectivity toward non-cancerous cells. The lead compounds were further assessed in vivo using a Danio rerio model to evaluate general toxicity and cardiotoxicity. In addition, ADME parameters were predicted for all compounds using biomimetic chromatography. Overall, compounds 9 and 17 emerged as promising small-molecule candidates for TNBC treatment, requiring further toxicological evaluation in more human-relevant in vivo models. Full article

Exosomes are nanoscale extracellular vesicles that carry disease-associated microRNAs (miRNAs) and represent promising biomarkers for cancer diagnosis. Triple-negative breast cancer (TNBC) lacks well-defined molecular markers, necessitating sensitive and integrable analytical approaches for TNBC-related exosomal miRNAs. In this study, exosomes were isolated from MDA-MB-231 TNBC cells using a paddle screw-based system designed to enhance mass transfer through active rotation, providing a mechanically driven isolation strategy that is compatible with miniaturized and microfluidic platforms. This dynamic isolation process enabled rapid and efficient exosome recovery within a short processing time. Three TNBC-associated miRNAs encapsulated in the isolated exosomes were quantitatively analyzed using polyadenylation tailing (poly(A) tailing) and specific bidirectional extension sequence-based assays combined with reverse transcription quantitative real-time PCR (RT-qPCR). The bidirectional extension (BDE) assay generated highly specific PCR templates, leading to improved amplification specificity and reduced background signals. The RT-qPCR analysis exhibited high sensitivity, wide dynamic range, and good reproducibility for all target miRNAs. Overall, these results demonstrate that the integration of a paddle screw-based exosome isolation module with an extension-based nucleic acid detection strategy provides a scalable and biosensor-compatible analytical framework for profiling TNBC-associated exosomal miRNAs, with potential applications in microfluidic liquid biopsy platforms and exosome-based cancer diagnostics. Full article

Breast cancer (BC) is a highly heterogeneous genetic disease, comprising several subtypes with distinct features that significantly influence prognosis and treatment outcomes. Among these subtypes, triple-negative breast cancer (TNBC) is particularly aggressive and makes it resistant to many standard therapies. Epigenetic mechanisms, including acetylation and deacetylation, are crucial in regulating gene expression and maintaining normal cellular functions and are closely associated with BC progression. In this context, the histone deacetylases sirtuins (SIRT1-7) regulate key biological processes like genomic stability, inflammation, cellular senescence, and metabolic functions, increasingly linked to cancer. In particular, SIRT1 shows dual roles, functioning both as a tumor suppressor or an oncogene, contributing to cancer initiation, progression, and metastasis as well as chemotherapy resistance. Despite extensive research in the past decade, the exact role of SIRT1 in BC, especially in TNBC, remains controversial. Recent findings suggest that SIRT1 can be modulated not only through pharmacological approaches but also using natural extracts, offering potential alternative or complementary therapeutic strategies. Additionally, SIRT1 activity is regulated by a complex network of miRNAs, highlighting the need for further investigation. This review aims to summarize recent studies to identify key insights into the role of SIRT1 and explore it as a potential therapeutic target in BC. Full article