Search Results (1,554)

Triple-negative breast cancer (TNBC), which is characterized by a lack of the estrogen receptor, the progesterone receptor, and HER2 expression, is the most aggressive breast cancer subtype and has a poor prognosis and high recurrence rates because of frequent chemotherapy resistance. As a crucial epigenetic regulator, DNA methylation modulates gene expression through aberrant methylation patterns, contributing to tumor progression and therapeutic resistance. Early diagnosis and treatment of TNBC are vital for its prognosis. The development of DNA methylation testing technology and the application of liquid biopsy provide technological support for early diagnosis and treatment. Additionally, preclinical and early-phase clinical studies suggest that epigenetic therapies targeting DNA methylation may hold promise for TNBC treatment, pending larger clinical trials. Furthermore, research on DNA methylation-based prognostic models enables personalized precision treatment for patients, helping to reduce unnecessary therapies and improve overall survival. The emerging role of DNA methylation patterns in predicting the therapeutic response and overcoming drug resistance is highlighted. In this narrative review, we integrate current research findings and clinical perspectives. We propose that DNA methylation presents promising research prospects for the diagnosis, treatment and prognosis prediction of TNBC. Future efforts should focus on translating methylation-driven insights into clinically actionable strategies, ultimately advancing precision oncology for this challenging disease. Full article

Background and Clinical Significance: Breast cancer is the most frequent malignancy in women. Metastatic breast cancer is considered a treatable but incurable condition, with a median overall survival of only 2–3 years. Among its subtypes, triple-negative breast cancer (TNBC) accounts for a high proportion of breast cancer-related deaths. It is characterized by an aggressive clinical course, early recurrence, and a strong propensity for visceral and brain metastases. Case Presentation: We report the case of a Caucasian woman who developed systemic disease recurrence with lung and mediastinal lymph node metastases, occurring two years after her primary diagnosis and treatment for TNBC. The patient received three months of chemotherapy combined with an adjuvant integrative protocol consisting of melatonin, cannabidiol, and oxygen–ozone therapy. This combined approach led to the complete disappearance of the lung nodules. Subsequently, stereotactic radiotherapy was performed and, in association with the ongoing integrative treatment, resulted in a significant reduction in mediastinal adenopathy. Introduction of immunotherapy, supported continuously by the same adjuvant strategy, achieved a complete and durable remission. Strikingly, the patient remained disease-free five years after the diagnosis of lung and mediastinal metastases. Conclusions: This clinical case highlights the potential benefit of using melatonin, cannabidiol, and oxygen–ozone therapy as part of an integrative approach in patients with aggressive metastatic TNBC. While it is not possible to establish causality from a single case, the sustained remission observed suggests that such unconventional adjuvant strategies could play a supportive role in enhancing the efficacy of standard oncologic therapies. Full article

Background: Triple-negative breast cancer (TNBC) is more likely to metastasise to the lungs than other breast cancer (BrCa) types, yet the molecular interactions within the tumour microenvironment (TME) at secondary sites remain poorly understood. Methods: This pilot study aimed to explore the metabolic crosstalk between MDA-MB-231 TNBC cells and MRC-5 lung fibroblasts within a co-culture system to replicate the lung metastatic TME. Co-cultures were also treated with Vitamin D or Vitamin E to evaluate the effects of these nutraceuticals on the metabolic crosstalk between TNBC cells and fibroblasts. Results: Our findings demonstrate that co-culture induced the activation of fibroblasts into cancer-associated fibroblasts (CAFs), evidenced by increased α-SMA and FAP expression. Metabolic profiling revealed that TNBC cells in co-culture displayed increased expression of enzymes associated with oxidative phosphorylation (OXPHOS) and glutamine metabolism, while fibroblasts exhibited a metabolic profile consistent with glycolysis and lactate metabolism. Vitamin D inhibited lactate metabolism and HIF-1α expression in fibroblasts while suppressing TCA cycle activity in cancer cells, suggesting a potential role in disrupting oncogenic metabolic crosstalk. Conversely, Vitamin E treatment was associated with increased expression of TCA cycle and oxidative metabolism-related markers in BrCa cells without significantly affecting fibroblast glycolysis. Such differential metabolic responses may contribute to metabolic heterogeneity within the tumour microenvironment. Conclusions: These results provide valuable insights into the metabolic dynamics of TNBC metastases in the lung TME and demonstrate that Vitamins D and E exert distinct effects on metabolic crosstalk between cancer cells and fibroblasts. These findings may have significant implications for the potential supplementation of Vitamins D and E in patients with metastatic TNBC and justify further in-depth analysis. Full article

Due to their therapeutic potential and effects on cells, exosomes derived from bovine colostrum (BCE) and milk (BME) are molecules that have been at the center of recent studies. Their properties include the ability to cross biological barriers, their natural biocompatibility, and their structure, which enable them to act as stable nanocarriers. Exosomes derived from milk and colostrum stand out in cancer prevention and treatment due to these properties. BMEs can be enriched with bioactive peptides, lipids, and nucleic acids. The targeted drug delivery capacity of BMEs can be made more efficient through these enrichment processes. For example, BME enriched with an iRGD peptide and developed using hypoxia-sensitive lipids selectively transported drugs and reduced the survival rate of triple-negative breast cancer (TNBC) cells. ARV-825-CME formulations increased antitumor activity in some cancer types. The anticancer effects of exosomes are supported by these examples. In addition to their anticancer activities, exosomes also exhibit effects that maintain immune balance. BME and BCE can regulate inflammatory responses with their miRNA and protein loads. These effects of BMEs have been demonstrated in studies on colon, breast, liver, and lung cancers. The findings support the safety and scalability of these effects. However, significant challenges remain in terms of their large-scale isolation, load heterogeneity, and regulatory standardization. Consequently, BMEs represent a new generation of biogenic nanoplatforms at the intersection of nutrition, immunology, and oncology, paving the way for innovative therapeutic approaches. Full article

Edible flowers have garnered increasing attention due to their high content of bioactive compounds, making them promising candidates for biomedical and functional food applications. This work evaluated the metabolomic data of fresh Rosa x hybrida petals, revealing seven types of metabolites, including amino acids, organic acids, vitamins, sugars, phenolic acids, and flavonoids. Notably, quercetin, kaempferol and their derivatives were the main flavonoids determined. Furthermore, in vitro studies were conducted to evaluate the potential antiproliferative effects against triple-negative breast cancer (TNBC). Thus, the methanolic extract derived from Rosa x hybrida petals demonstrated significant antitumoral activity against both sensitive and resistant TNBC cells, as evidenced by reduced MTT metabolization, colony formation, and wound healing activity. Furthermore, the cell death mechanism associated with the petal extract was studied. The antiproliferative activity was mediated by reactive oxygen species generation, triggering cell death mechanisms such as apoptosis and autophagy. In conclusion, these results propose Rosa x hybrida could be a new tool for nutraceuticals and functional food production. Full article

Background: Recombinant human arginase (rhArg) has been proven to exhibit an anticancer effect via arginine starvation. To further improve the efficacy of rhArg, we examined the feasibility of a combination strategy with Bcl-2 inhibitors (ABT263 and ABT199) or an antidiabetic drug (metformin) and investigated the mechanistic basis for these strategies. Methods: The combination effects were evaluated in a panel of human cancer cell lines modeling pancreatic ductal carcinoma (PDAC), triple-negative breast cancer (TNBC), colorectal cancer (CRC) and glioblastoma (GBM). Western blot analysis was used to evaluate the expression of apoptotic and cell cycle markers. MTT assay was used to evaluate the combination efficacy. Flow cytometric assays were used to investigate the apoptotic and cell cycle effects. Results: The combination of rhArg with sublethal doses of ABT263 significantly induced dose-dependent apoptosis, with elevated expression of apoptotic markers and a CI of 0.47 in U251. The combination inhibited CDK2 and cyclin A expression, indicating that the observed synergy also resulted from cell cycle arrest. We also found that rhArg + metformin was synergistic in a time-dependent manner. Compared to other amino acid depletion agents, rhArg + ABT263 was the most favorable combination pair. Conclusions: The combination of rhArg and ABT263 enhanced apoptosis and cell cycle arrest, demonstrating a potential broad-spectrum antitumor strategy. Full article

Background: Triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression, is associated with increased BRCA1/2 mutation rates. Extracellular vesicles (EVs) play a pivotal role in TNBC progression. This study aimed to analyze BRCA1/2 mutations and identify EV-related biomarkers for TNBC by employing TNBC-related datasets and EV-related genes (EVRGs). Methods: Initially, BRCA1/2 mutations in TNBC patients were examined. Differentially expressed EVRGs (DE-EVRGs) were identified by integrating the results of both differential expression analysis and weighted gene co-expression network analysis (WGCNA). Biomarkers were identified using Receiver Operating Characteristic (ROC) and Kaplan–Meier (K–M) analyses. Finally, functional enrichment, drug prediction, molecular docking, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analyses were performed. Results: Waterfall plots indicated that TP53 exhibited the highest mutation frequency in both the mutation (MUT) and wild-type (WT) group. Four distinct types of immune cells (for example, eosinophils and neutrophils) showed significantly elevated expression levels in the WT group. Notably, PLA2G5 was identified as a biomarker of TNBC and its expression was significantly lower in TNBC (p = 0.0025). Functional analysis demonstrated that PLA2G5 is enriched in the “drug metabolism cytochrome P450” pathway. Finally, 20 drugs targeting PLA2G5 were identified, among which leukotriene C4 demonstrated a binding affinity of −7.2 kcal/mol. This finding suggests that leukotriene C4 has potential therapeutic applications for the treatment of TNBC. Conclusions: Our study found significant differences between the MUT and WT groups, identifying PLA2G5 as a biomarker for TNBC and offering a theoretical basis for TNBC treatment. Full article

Background: Triple-negative breast cancer (TNBC) remains primarily treated with chemotherapy due to the lack of effective therapeutic targets, but this approach carries significant systemic toxicity and a high risk of drug resistance. Curcumin (Cur), despite its multifaceted antitumor activity, faces limitations in clinical application due to poor water solubility and weak targeting properties. This study aims to develop a folate/mitochondria dual-targeted curcumin–copper chelate liposome (Cu-Cur DTLPs) formulation that enables copper accumulation within tumor cells and induces copper-mediated cell death, thereby providing an effective and relatively low-toxicity therapeutic strategy for triple-negative breast cancer. Methods: Curcumin–copper chelates (Cu-Cur) were first synthesized and characterized using mass spectrometry, NMR, and infrared spectroscopy. Subsequently, dual-targeted liposomes (Cu-Cur DTLPs) were prepared via the thin-film dispersion method, with systematic evaluation of particle size, zeta potential, encapsulation efficiency, and in vitro release profiles. In vitro cytotoxicity was assessed against 4T-1 and MDA-MB-231 cells using the MTT assay. In a 4T-1 tumor-bearing BALB/c mouse model, comprehensive evaluation of targeting efficiency, antitumor efficacy, and mechanisms of action was conducted via in vivo imaging, tumor volume monitoring, immunohistochemistry (detecting FDX1 and DLAT proteins), and TUNEL staining. Results: Cu-Cur DTLPs with a uniform particle size of approximately 104.4 nm were successfully synthesized. In vitro and in vivo studies demonstrated that compared to free curcumin and conventional liposomes, Cu-Cur DTLPs significantly enhanced drug accumulation in tumor tissues and exhibited effective tumor growth inhibition. Mechanistic studies confirmed that this formulation specifically accumulates copper ions within tumor cells, upregulates FDX1, promotes DLAT oligomerization, and induces mitochondrial dysfunction, thereby driving copper death. TUNEL staining ruled out apoptosis as the primary mechanism. Safety evaluation revealed no significant toxicity in major organs. Conclusions: The Cu-Cur DTLPs developed in this study effectively induce copper-mediated death in TNBC through a dual-targeted delivery system, significantly enhancing antitumor activity with favorable safety profiles. This establishes a highly promising novel nanotherapeutic strategy for TNBC treatment. Full article

Breast cancer is a complex and highly heterogeneous disease, and its management is increasingly moving towards the principles of precision medicine. In this context, the androgen receptor (AR) has emerged as a promising therapeutic target, particularly within the challenging subgroup of triple-negative breast cancers (TNBCs) that express it. This scoping review provides a comprehensive and detailed analysis of the multifaceted role of AR in breast cancer. We delve into its intricate molecular structure, its differential function in ER-positive vs. TNBC subtypes, and the detailed molecular mechanisms that govern its activity. We provide a thorough examination of the landmark clinical trials with antiandrogen agents, including not only enzalutamide but also other first- and second-generation compounds, and discuss the emerging data on their efficacy. Furthermore, we will explore the critical challenges that hinder their widespread clinical adoption, such as primary and acquired resistance mechanisms, the need for robust predictive biomarkers, and the heterogeneity of AR expression. Finally, we outline future research directions, focusing on novel combination therapies and the development of next-generation agents and predictive tools to optimize patient selection and improve clinical outcomes. Full article

Background: The UGT1A1 gene is associated with the toxicity caused by SN38, the cytotoxic component of Sacituzumab govitecan (SG) used in the treatment of metastatic triple-negative breast cancer (mTNBC), among other approved indications. In this study, we aimed to analyze the effect of UGT1A1*28 allele on the safety and, secondarily, the effectiveness of SG in mTNBC. Methods: This was a multicenter, ambispective study that included patients treated with SG for mTNBC. Genotyping for UGT1A1*28 was performed using real-time polymerase chain reaction (PCR). Adverse events (AEs) of grade ≥ 2 during the first three cycles were compared between patients who were homozygous mutant (UGT1A1*28/*28) and those with wild-type (WT) or heterozygous genotypes. Effectiveness between the two groups was also compared using progression-free survival (PFS) and overall survival (OS) assessed with the Kaplan–Meier method. Results: A total of 81 patients were included: 37.0% were WT, 55.6% heterozygous, and 7.4% homozygous mutant. All UGT1A1 *28/*28 patients experienced grade ≥ 2 AEs (100% vs. 69.3%; p = 0.109), with a statistically significant association in the case of febrile neutropenia (33.3% vs. 6.7%; p = 0.025), and a trend towards higher rates of anemia and diarrhea (50.0% vs. 17.3%; p = 0.053). Genotype did not influence PFS or OS; however, dose reductions were associated with better survival outcomes. Conclusions: This real-world study shows a correlation between toxicity and the presence of the UGT1A1*28 mutation in patients treated with SG for mTNBC. Improving treatment tolerability through dose reductions may enhance SG effectiveness. These findings support the implementation of UGT1A1 genotyping in routine clinical practice. Full article

Breast cancer is a significant public health concern, with triple-negative breast cancer (TNBC) being the most aggressive subtype characterized by considerable heterogeneity and the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Currently, there are no practical alternatives to chemotherapy, which is associated with a poor prognosis. Therefore, developing new treatments for TNBC is an urgent need. Reactive oxygen species (ROS) and redox adaptation play central roles in TNBC biology. Targeting the redox state has emerged as a promising therapeutic approach, as it is vital to the survival of tumors, including TNBC. Although TNBC does not produce high levels of ROS compared to ER- or PR-positive breast cancers, it relies on mitochondria and oxidative phosphorylation (OXPHOS) to sustain ROS production and create an environment conducive to tumor progression. As a result, novel treatments that can modulate redox balance and target organelles essential for redox homeostasis, such as mitochondria, could be promising for TNBC—an area not yet reviewed in the current scientific literature, thus representing a critical gap. This review addresses that gap by synthesizing current evidence on TNBC biology and its connections to redox state and mitochondrial metabolism, with a focus on innovative strategies such as metal-based compounds (e.g., copper, gold), redox nanoparticles that facilitate anticancer drug delivery, mitochondrial-targeted therapies, and immunomodulatory peptides like GK-1. By integrating mechanistic insights into the redox state with emerging therapeutic approaches, I aim to highlight new redox-centered opportunities to improve TNBC treatments. Moreover, this review uniquely integrates mitochondrial metabolism, redox imbalance, and emerging regulated cell-death pathways, including ferroptosis, cuproptosis, and disulfidptosis, within the context of TNBC metabolic heterogeneity, highlighting translational vulnerabilities and subtype-specific therapeutic opportunities. Full article

Background/Objectives: Breast cancer is a prevalent and heterogeneous disease with multiple subtypes, which are defined by characteristics such as molecular biomarkers and metastatic status. This study aimed to profile the metabolic activity of various breast cancer subtypes, both with and without chemotherapy (doxorubicin) application. Methods: Six human breast cell lines were evaluated, two non-tumorigenic controls and four cancerous lines. The cancer lines were clustered as primary-derived, metastasis-derived, triple-negative (TNBC), and strong hormone receptor-positive (ER+/PR+) and analyzed using the Biolog phenotype mammalian microarrays (PM-M1 to PM-M8) to assess metabolic activity via NADH production under a wide array of substrate parameters. Results: Unique metabolic profiles emerged across the subtypes and clusters; the TNBC and metastatic cells demonstrated enhanced utilization of glycolytic and anaerobic substrates consistent with the Warburg effect. The ER+/PR+ cells showed heightened glucose utilization and unique sensitivity to metabolic effectors and doxorubicin. Additionally, significant metabolic differences were observed in nucleoside and amino acid utilization between cancer and control cells, particularly in metastatic and TNBC lines. Conclusions: Our findings reveal the profound metabolic diversity among breast cancer subtypes and highlight distinct substrate dependencies for proliferation. The results additionally provide a framework for developing metabolic biomarkers and targeted therapies for chemotherapy resistance in breast cancer subtypes. Full article

Background: Lactate Dehydrogenase C (LDHC) is a promising therapeutic target due to its highly tumor-specific expression, immunogenicity, and oncogenic functions. We previously showed that LDHC silencing in triple-negative breast cancer (TNBC) cells enhances treatment response to DNA-damage response-related drugs, supporting its therapeutic potential. However, no selective LDHC inhibitors exist, highlighting the need for innovative targeting strategies. Methods: We assessed the physicochemical properties and evaluated the delivery efficiency, anti-tumor activity, and safety of four cell-penetrating peptides (CPPs)—R10, 10R-RGD, cRGD-10R, and iRGD-10R—for siRNA-mediated LDHC silencing in TNBC. Clonogenic assays were used to evaluate effects on olaparib sensitivity, and TNBC zebrafish xenografts were utilized to study in vivo anti-tumor activity. Results: All CPP:siRNA complexes formed uniform nanocomplexes (129–168 nm) with low polydispersity indices (<0.25) and positive zeta potentials (+6.47 to +29.6 mV). Complexes remained stable in human serum for 24 h and showed no significant cytotoxicity in TNBC and non-cancerous cell lines. The 10R-RGD and cRGD-10R:siLDHC complexes achieved 40% LDHC protein knockdown, reduced TNBC clonogenicity by 30–36%, and enhanced olaparib sensitivity. Treatment of TNBC zebrafish xenografts with 10R-RGD or cRGD-10R:siLDHC complexes significantly reduced tumor growth by approximately 50% without major toxicity. Conclusions: These results demonstrate that CPP-mediated siRNA delivery enables selective LDHC silencing with tumor growth inhibition in triple-negative breast cancer models. This approach represents a novel, effective, and safe proof-of-concept therapeutic strategy to target LDHC, with potential translational relevance as a standalone therapy or in combination with common anti-cancer drugs. Full article

An unmet challenge in managing breast cancer is treatment failure due to resistance to apoptosis-inducing chemotherapies. Thus, it is important to identify novel non-apoptotic therapeutic agents. Several non-apoptotic programmed cell death pathways utilize specific cellular signaling events to trigger lytic and pro-inflammatory cell death, examples of which are pyroptosis and necroptosis. Our study illustrates that ophiobolin A (OpA) is an anti-cancer agent that triggers lytic cell death in breast cancer cells, including triple-negative breast cancer (TNBC). This study reveals that OpA induces typical pyroptosis-like characteristics, including cellular swelling, plasma membrane rupture, GSDMD cleavage, and release of cytokines in breast cancer cells. However, the additional involvement of RIPK1 and induction of RIPK3 clustering in select cell lines suggest that multiple pathways may be triggered upon OpA treatment. The induction of pro-inflammatory cell death suggests potential applications for OpA in cancer treatment. Full article

Breast cancer subtypes are known to have important pathobiological and clinical features. For example, triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant breast cancer subtypes, lacking hormone and HER2 targets. Increasing evidence suggests that circular RNAs (circRNAs) and their N6-methyladenosine (m⁶A) modifications play critical roles in cancer biology through the regulation of gene expression, stability, and signaling networks. This study aimed to identify m⁶A methylation patterns in circRNAs among breast cancer subtypes, explore their potential biological functions, and assess their diagnostic and prognostic relevance compared with luminal breast cancer subtypes. Genome-wide profiling of m⁶A-modified circRNAs was conducted in TNBC and luminal breast tumor samples using methylated RNA immunoprecipitation followed by microarray analysis. Differential methylation and expression analyses were integrated with pathway enrichment, survival correlation, and receiver operating characteristic (ROC) curve assessments to identify subtype-specific and clinically relevant circRNA candidates. Distinct m⁶A circRNA methylation signatures were identified across breast cancer subtypes, with TNBC showing enrichment in pathways related to Wnt/β-catenin, CDC42 GTPase signaling, and cytoskeletal remodeling. Several circRNAs, including those derived from ZBTB16, DOCK1, METTL8, and VAV3, exhibited significant hypermethylation and high diagnostic accuracy (AUC > 0.80). Survival analyses revealed associations between circRNAs from key host genes and overall or relapse-free survival, suggesting prognostic potential. These findings uncover subtype-specific m⁶A circRNA methylation landscapes that may contribute to tumor aggressiveness and heterogeneity. Identified circRNAs represent candidates for investigation as biomarkers for subtype classification and prognosis and may inform future research into epigenetic and post-transcriptional therapeutic targets in breast cancer. Full article