Search Results (1,868)

The past decade has witnessed an unprecedented transformation in breast cancer management, driven by parallel advances in targeted therapies, immunomodulation, drug-delivery technologies, and molecular diagnostic tools. This review summarizes the key achievements of 2015–2025, encompassing all major biological subtypes of breast cancer as well as technological innovations with substantial clinical relevance. In hormone receptor-positive (HR+)/HER2− disease, the integration of CDK4/6 inhibitors, modulators of the PI3K/AKT/mTOR pathway, oral Selective Estrogen Receptor Degraders (SERDs), and real-time monitoring of Estrogen Receptor 1 (ESR1) mutations has enabled clinicians to overcome endocrine resistance and dynamically tailor treatment based on evolving molecular alterations detected in circulating biomarkers. In HER2-positive breast cancer, treatment paradigms have been revolutionized by next-generation antibody–drug conjugates, advanced antibody formats, and technologies facilitating drug penetration across the blood–brain barrier, collectively improving systemic and central nervous system disease control. The most rapid progress has occurred in triple-negative breast cancer (TNBC), where synergistic strategies combining selective cytotoxicity via Antibody-Drug Conjugates (ADCs), DNA damage response inhibitors, immunotherapy, epigenetic modulation, and therapies targeting immunometabolic pathways have markedly expanded therapeutic opportunities for this historically challenging subtype. In parallel, photodynamic therapy has emerged as an investigational and predominantly local phototheranostic approach, incorporating nanocarriers, next-generation photosensitizers, and photoimmunotherapy capable of inducing immunogenic cell death and modulating antitumor immune responses. A defining feature of the past decade has been the surge in patent-driven innovation, encompassing multispecific antibodies, optimized ADC architectures, novel linker–payload designs, and advanced nanotechnological and photoactive delivery systems. By integrating data from clinical trials, molecular analyses, and patent landscapes, this review illustrates how multimechanistic, biomarker-guided therapies supported by advanced drug-delivery technologies are redefining contemporary precision oncology in breast cancer. The emerging therapeutic paradigm underscores the convergence of targeted therapy, immunomodulation, synthetic lethality, and localized immune-activating approaches, charting a path toward further personalization of treatment in the years ahead. Full article

Background: Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, characterized by high genomic instability, metabolic stress, and limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising vulnerability in TNBC, yet its subtype-specific regulatory landscape remains insufficiently defined. Methods: Using transcriptomic (METABRIC, TCGA, GEO) and proteomic (CPTAC) datasets, ferroptosis-related genes were profiled across PAM50 breast cancer subtypes. Differential expression, univariate Cox regression, LASSO modeling, survival analyses, GSEA, and dimensionality reduction (PCA, t-SNE) were applied. A Ferroptosis Index (FI) was calculated using β-coefficients from the Cox/LASSO regression model. Single-cell RNA-seq data was used to map ferroptosis-associated signature across tumor and microenvironmental compartments. Results: Basal-like tumors exhibited the strongest ferroptosis-associated transcriptional shift, characterized by upregulation of ACSL4 and EZH2 and downregulation of AR, GPX4, and CIRBP. Sixteen ferroptosis-related genes were associated with overall survival, forming a ferroptosis-associated signature. The FI was significantly higher in Basal-like tumors, indicating elevated ferroptosis-associated transcriptional state. GSEA revealed enrichment of cell cycle, mitotic, cytoskeletal, and metabolic stress pathways. Single-cell analysis demonstrated expression of ferroptosis markers across cancer epithelial, stromal, and myeloid populations. Conclusions: Basal-like tumors harbor a distinct ferroptosis-associated transcriptional state linked to tumor aggressiveness and poor prognosis. These findings provide a biologically grounded framework for ferroptosis-related stratification and support future functional and translational studies targeting ferroptosis vulnerabilities in aggressive breast cancer. Full article

Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. Although cisplatin is widely used in chemotherapy, its clinical efficacy is often limited by adverse effects and resistance. Thus, natural bioactive compounds are gaining attention as complementary therapeutic agents. This study aimed to evaluate the anti-tumor effects of Annona muricata leaf extract on murine breast cancer 4T1 cells, used alone or in combination with cisplatin. Cisplatin induced intrinsic apoptosis through mitochondrial membrane disruption, up-regulation of the Bax gene and inhibition of the PI3K/AKT/mTOR signaling pathway. Cisplatin also promoted hypoxia by HIF1α gene expression, inflammation by TNFα and IL-6 gene expression, and induced cell cycle arrest at the sub-G1 phase by down-regulation of cyclin D1 and cyclin E1 genes. Annona muricata leaf extract triggered autophagy-mediated 4T1 cell death through mainly mTOR down-regulation and increased expression of Beclin1 and LC3 genes. It also induced cell cycle arrest at sub-G1 and S phases in a concentration- and time-dependent manner. When, combined with cisplatin, Annona muricata extract shifts the cell death pathway from intrinsic apoptosis toward autophagy by reduced caspase-3 gene expression and activity and enhanced LC3-I to LC3-II conversion. Moreover, Annona muricata extract attenuated cisplatin-induced inflammation by inhibiting TNFα and IL-6 gene expression and reinforced cell cycle arrest through suppression of the cyclin D1 gene. In conclusion, our results suggest that Annona muricata leaf extract exerts significant anti-tumor activity in breast cancer cells and may enhance cisplatin efficacy by shifting the signaling pathway from intrinsic apoptosis toward autophagy, and attenuating inflammation-related effects, supporting its potential use as a complementary therapeutic strategy. Full article

Adipose tissue plays a crucial role in breast cancer (BC) progression by actively modulating the tumor microenvironment. We investigated how tumor proximity modifies adipose tissue by analyzing selected adipose-related and prognosis-associated markers in explants from BC patients and healthy donors. Explants were categorized by proximity to the tumor as adjacent (less than 2 cm), distant (over 2 cm), alongside normal explants (controls). FABP4 and vimentin expression was increased in proximity to the tumor, while caveolin-1, CD44, MMP9, and adiponectin showed minimal or no changes. Conditioned media (CM) from adjacent and normal explants were then assessed for their effects on tumorigenic traits in hormone-receptor-positive breast cancer (HR+ BC) and triple-negative breast cancer (TNBC) cell lines. Adjacent-CM enhanced migration, induced cytoskeletal remodeling, reduced adhesion, and promoted an elongated, motile phenotype in T47D cells. Poor-prognosis markers (caveolin-1, vimentin, CD44) were upregulated in at least one HR+ BC model, whereas Nanog and KLF4 showed modest variation. In TNBC cells, both normal- and adjacent-CM partially shifted MDA-MB-231 morphology toward a more epithelial-like state, decreasing caveolin-1 levels, while adjacent-CM increased MMP9 expression. Overall, these results reveal that adipose tissue-derived soluble factors exert significant and subtype-dependent effects on BC tumorigenicity. Full article

Breast cancer remains a major global health challenge, with treatment access further constrained during the COVID-19 pandemic, particularly in resource-limited settings. This study evaluates the in vitro effects of hypofractionated versus conventionally fractionated radiotherapy on three breast cell lines: MCF-7 (oestrogen receptor-positive, ER⁺/PR⁺), MDA-MB-231 (triple-negative: ER⁻/PR⁻/HER2⁻), and MCF-10A (non-tumorigenic mammary epithelial). Cells were exposed to cobalt-60 γ-rays, and radiobiological endpoints assessed included clonogenic survival, α/β ratios, adaptive responses, migration, invasion, and cytotoxicity through lactate dehydrogenase assays. The α/β ratios ranged from 2.5 to 5.4 Gy across breast cancer subtypes. Hypofractionation reduced survival in hormone receptor-positive cells, whereas triple-negative cells exhibited increased survival. Adaptive radiation responses enhanced viability across all cell lines, while non-cancerous MCF-10A cells demonstrated reduced migration following treatment. These findings suggest that hypofractionated radiotherapy may be beneficial in hormone receptor-positive breast cancer, while triple-negative disease may show a trend toward different responses, although this was not statistically significant (MDA-MB-231, p = 0.290). The results underscore the importance of tailoring fractionation strategies to breast cancer subtype and highlight the translational potential of preclinical radiobiology in guiding personalised radiation oncology approaches. Full article

MicroRNAs are key post-transcriptional regulators in breast cancer, but their time-dependent dynamics and downstream oncogenic effects are not fully understood. miR-548c-3p has been proposed as a tumor suppressor, yet its temporal behavior and impact on cell cycle drivers remain unclear. This study investigated the time-dependent expression of miR-548c-3p and its post-transcriptional regulation of E2F3 and FOXM1 in MCF-7 breast cancer cells. Cells were analyzed at multiple time points (2–72 h) by quantitative real-time PCR to assess dynamic changes in miR-548c-3p, E2F3, and FOXM1 mRNA levels. Bioinformatic validation using TCGA-BRCA datasets and public platforms evaluated gene expression, promoter methylation, and prognostic significance. miR-548c-3p showed a progressive time-dependent decline, with the lowest levels at 72 h, whereas E2F3 and FOXM1 were significantly upregulated over time, supporting a post-transcriptional derepression mechanism. TCGA-based analyses confirmed overexpression and hypomethylation of E2F3 and FOXM1 in breast cancer, particularly in triple-negative tumors, and high expression of both genes was associated with poor survival. These findings indicate that time-dependent loss of miR-548c-3p contributes to E2F3 and FOXM1 activation through a post-transcriptional regulatory mechanism, highlighting this miRNA–oncogene axis as a potential prognostic signature and therapeutic target in breast cancer. Full article

Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) have transformed cancer therapy for patients harbouring homologous recombination repair (HRR) deficiencies, notably BRCA1/2 mutations. However, resistance to PARPi remains a clinical challenge, with restoration of BRCA1 function via hypomorphic variants representing an understudied scenario. Methods: Here, we engineered a doxycycline-inducible BRCA1 expression system in the BRCA1-mutant, triple-negative breast cancer cell line MDAMB436, permitting controlled analysis of functionally distinct BRCA1 hypomorphs in vitro and in vivo. Results: Among multiple BRCA1 variants generated—including RING, coiled-coil, and BRCT domain mutants—only overexpression of the ∆exon11 hypomorph robustly conferred resistance to olaparib and carboplatin, with drug sensitivity correlating to ∆exon11 expression levels. While ∆exon11 BRCA1 mediated HRR restoration, its efficiency was consistently lower than full-length BRCA1, as measured by RAD51 foci formation and interaction with repair partners such as PALB2. In vivo, tumours expressing Δexon11 BRCA1 exhibited only partial resistance to olaparib compared to those expressing full-length BRCA1. Importantly, the combination of olaparib and the ATR inhibitor, ceralasertib, overcame ∆exon11-mediated resistance, impairing RAD51 foci formation in ∆exon11-expressing cells. Conclusions: Our findings identify a dose-dependent, hypomorphic HRR restoration by ∆exon11 BRCA1, help explain the variable resistance observed in BRCA1-mutant pre-clinical models expressing this hypomorph, and propose ATR inhibition in combination with PARPi as a clinical strategy to counteract therapeutic resistance mediated by ∆exon11 BRCA1 hypomorphs. Full article

Breast cancer is a significant cause of death worldwide. Recent research has focused on identifying natural compounds for developing effective cancer treatments. Resiniferatoxin, a transient receptor potential vanilloid 1 (TRPV1) agonist, is a common diterpene in Euphorbia bicolor Engelm. & A. Gray (Euphorbiaceae), a plant native to the southern United States that has not been studied before. We investigated the antiproliferative activities and mechanisms of action of E. bicolor xylene extract in estrogen receptor-positive T47D and triple-negative MDA-MB-231 cell lines. The extract significantly reduced the viability of T47D and MDA-MB-231 cells in a dose-dependent manner. In MDA-MB-231 cells, the extract induced apoptosis via intracellular calcium overload, triggered by TRPV1 activation. This effect was diminished by the TRPV1 antagonist capsazepine and the calcium chelator BAPTA-AM. Intracellular calcium influx was confirmed through Fura-2 AM staining, revealing that E. bicolor phytochemicals activated TRPV1 in MDA-MB-231 cells. Treatment of T47D cells with E. bicolor xylene extract resulted in apoptosis associated with reactive oxygen species (ROS) generation (10-fold higher in T47D cells than in MDA-MB-231 cells) and mitochondrial calcium overload. These effects were significantly blocked when cells were pretreated with N-acetyl-l-cysteine (NAC), a ROS inhibitor. Both cell lines underwent apoptosis via multiple mitochondrial- and endoplasmic reticulum stress–mediated pathways. This was supported by the activation of caspases 3, 8, and 9; increased expression of FAS, XBP1s, and CHOP; upregulation of BAX; and downregulation of BCL-2. In addition, PI3K, AKT, and pAKT protein expressions were also reduced in both cell lines, indicating downregulation of PI3K/Akt signaling pathway. Phytochemicals in E. bicolor xylene extract could become promising ingredients for developing breast cancer therapeutics. 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

Background/Objectives: Breast cancer is the most common neoplasm among women and remains the leading cause of cancer-related mortality in the female population worldwide. Tumor cells exist within a highly oxidative microenvironment, which promotes the formation of substantial amounts of lipid peroxides. However, the clinical significance of circulating lipid peroxides in breast cancer is still not well understood. Methods: In this study, we quantified systemic lipid peroxide levels in plasma samples from 408 breast cancer patients and examined their associations with key clinicopathological parameters to evaluate their potential as disease biomarkers. Data are reported as relative light units (RLU). Results: Our findings revealed significantly higher lipid peroxide levels in HER2-amplified tumors compared with estrogen-receptor-positive tumors (1,133,494 ± 102,409 RLU vs. 951,883 ± 47,535 RLU; p = 0.0438). Elevated levels were also observed in patients with triple-negative breast cancer relative to those with Luminal A (1,163,323 ± 109,640 RLU vs. 875,633 ± 49,601 RLU; p = 0.0356) and Luminal B tumors (1,163,323 ± 109,640 RLU vs. 1,071,779 ± 98,329 RLU; p = 0.0254). In addition, increased lipid peroxidation was detected in patients with high-grade tumors (G3: 1,141,035 ± 101,045 RLU vs. G1–G2: 949,658 ± 46,119 RLU; p = 0.0346) and in those classified as at high risk of recurrence or death compared with low-risk patients (1,209,530 ± 95,396 RLU vs. 978,318 ± 229,526 RLU; p = 0.0054). Overweight patients also exhibited higher lipid peroxide levels than eutrophic individuals (1,131,233 ± 59,633 RLU vs. 820,772 ± 57,653 RLU; p = 0.0142). Conclusions: Collectively, these results suggest that circulating lipid peroxides may serve as potential biomarkers for recurrence and death risk in breast cancer, particularly among patients with more aggressive tumor phenotypes. 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

The targeting of cyclin dependent kinase 8 (CDK8) as a potential strategy for cancer treatment has been of interest since the identification of CDK8 as an oncogene product. In this report, we communicate the results of our continuing investigation into the effects of CDK8 inhibitor on triple-negative breast cancer cell line MDA-MB-468. Here, we demonstrate that inhibition of CDK8 decreases phosphorylation of CDK8 substrates E2 promoter binding factor 1 (E2F1) at serine 375 and signal transducer and activator of transcription 3 (STAT3) at serine 727 in these cells. Additionally, luciferase expression was increased in E2F1-responsive luciferase plasmid-transfected cells. Expression of E2F1 transcription target, the proapoptotic protein p73, was increased, and expression of antiapoptotic protein myeloid cell leukemia sequence 1 (Mcl-1) was decreased in CDK8 inhibitor-treated cells. We also demonstrate that knockdown of STAT3 or disruption of STAT3 function in MDA-MB-468 cells opposes the effects of CDK8 inhibition on Mcl-1. Together, these results suggest that CDK8 inhibitor treatment can modulate the expression of apoptosis-related proteins p73 and Mcl-1 and continues to highlight the potential cooperative effects of E2F1 and STAT3 in the activity of CDK8 inhibitor against MDA-MB-468 triple-negative breast cancer cells. 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