Mammalian genomes are pervasively transcribed into long noncoding RNAs (lncRNAs), whose functions and modes of action remain poorly understood. EPB41L4A-AS1 is an evolutionarily conserved, broadly and highly expressed lncRNA that produces the H/ACA snoRNA SNORA13 from one of its introns. We studied the consequences of EPB41L4A-AS1 perturbation in breast cancer cells and found that it acts both in cis, to enhance transcription of the proximal EPB41L4A gene and additional genes in its two flanking topologically associated domains, and in trans by broadly regulating gene expression, including expression of snoRNAs, transcription of genes involved in nucleolar biology and the distribution of nucleolar proteins. These effects are phenocopied by the loss of SUB1, an interactor of EPB41L4A-AS1, and are observed following transient perturbations of EPB41L4A-AS1 that do not affect steady-state SNORA13 levels or the rRNA modification it helps install. Exogenous expression of the full-length EPB41L4A-AS1 locus but not SNORA13 expression can rescue the trans-acting transcriptional effects of its perturbation. The EPB41L4A-AS1 gene is thus a versatile locus producing RNA molecules acting on multiple levels for key cellular functions.

Sensory neurons turn cues from breast cancer cells into a dense stromal barrier against antitumor immunity.

Multitarget-directed ligands offer a promising strategy for overcoming tumor complexity through simultaneous modulation of complementary oncogenic pathways. In this work, a novel (E)-6-(3-(4-methyl-2-thioxo-2,3-dihydrothiazol-5-yl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (compound 6) was synthesized and evaluated as a dual inhibitor of tubulin polymerization and tumor-associated carbonic anhydrases (CAs) IX and XII. Compound 6 displayed potent antiproliferative activity, particularly against MDA-MB-231 triple-negative breast cancer cells (IC50 = 0.37 µM), with excellent selectivity toward non-tumorigenic cells. Mechanistic studies demonstrated strong tubulin polymerization inhibition (IC50 = 3.40 ± 0.09 µM) and submicromolar inhibition of CA IX (IC50 = 0.102 ± 0.005 µM) and CA XII (IC50 = 0.213 ± 0.004 µM), accompanied by downregulation of CA-IX and CA-XII protein expression. Cellular investigations revealed pronounced G2/M phase arrest and apoptosis induction via mitochondrial signaling and caspase activation. Anti-angiogenic activity was supported by inhibition of endothelial migration and concentration-dependent suppression of VEGFR-2 (Tyr1175) phosphorylation in HUVEC cells. Human liver microsomal assays indicated measurable metabolic stability, while molecular docking and in silico ADMET predictions supported target engagement and drug-like properties. Collectively, these findings identify compound 6 as a promising multitarget anticancer lead integrating antimitotic, metabolic, and anti-angiogenic mechanisms.

Breast cancer is a leading cause of cancer-related mortality in women, necessitating new treatment strategies. Curcumin (Cur), a natural polyphenol, and gemcitabine (Gem), a standard chemotherapeutic, were investigated for their combined anticancer effects. We hypothesized that Cur sensitizes breast cancer cells to Gem via reactive oxygen species (ROS)-mediated apoptosis, and that this effect is associated with selective oxidative vulnerability in malignant cells compared to normal breast epithelial cells. MCF-7 (hormone receptor-positive) and MDA-MB-231 (triple-negative) cells were treated with Cur and Gem alone or in combination. Normal breast epithelial MCF-10A cells were included to evaluate therapeutic selectivity. Cell viability (MTT), apoptosis (Annexin V/PI), oxidative stress (TOS/TAS), intracellular ROS generation (DCFH-DA assay), mitochondrial membrane potential (ΔΨm) (JC-1 staining), caspase activation, synergy (Bliss/HSA/Chou-Talalay), VEGF secretion (ELISA), and transcriptomic changes (RNA-Seq) were assessed. Cur and Gem showed dose-dependent cytotoxicity. Combination treatment demonstrated strong synergistic activity, significantly enhancing apoptosis, oxidative stress, and caspase activation. Direct quantification of intracellular ROS revealed marked ROS accumulation in MCF-7 and MDA-MB-231 cells following combination treatment, whereas MCF-10A cells exhibited only modest oxidative changes. JC-1 analysis demonstrated substantial mitochondrial depolarization in breast cancer cells, which was largely reversible by ROS scavenging and minimal in MCF-10A cells. VEGF secretion was markedly suppressed. Transcriptomic analysis revealed profound alterations in apoptosis, cell cycle, and angiogenesis-related pathways, with more pronounced transcriptional reprogramming observed in the triple-negative subtype. Cur synergistically enhances Gem’s efficacy in breast cancer cells through ROS-mediated apoptosis and anti-angiogenic effects, characterized by cancer-selective ROS amplification and mitochondrial membrane depolarization, supporting its potential as a combination therapy, particularly for triple-negative breast cancer.

Dynamic Intracellular Trafficking of the Low Molecular Weight Protamine in Breast Cancer Cells.

In this study, an aqueous extract of Spirulina platensis was utilized as a reducing and stabilizing agent for the green synthesis of silver-zinc oxide nanocomposites (Ag-ZnO). The S. platensis extract was optimized at a concentration of 0.5%, stored at 4°C and centrifuged at 6000 rpm for 5 min. Ultraviolet-visible spectroscopy of the extract showed a broad absorbance band in the 330- to 380-nm region and a shoulder in the 520- to 620-nm range, corresponding to bioactive metabolites. The formation of silver-zinc oxide nanocomposites was confirmed by characteristic absorbance in the 300- to 400-nm region under optimized conditions. Particle size analysis using a Zetasizer revealed an average particle size of approximately 204 nm with a polydispersity index of 0.28. Functional groups, crystallinity, and surface morphology were characterized using Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy. Due to increasing concerns over antibiotic resistance, the antibacterial potential of the synthesized nanocomposites was evaluated by the disk diffusion method showing a maximum zone of inhibition of 35 ± 0.4 nm against Pseudomonas aeruginosa at 13 μg/mL. The Ag-ZnO nanocomposites exhibited a notable antioxidant activity, indicating a concentration-dependent DPPH radical scavenging activity with a maximum inhibition of 67.3% at 517 nm, compared to 60.12 for ascorbic acid. Furthermore, cytotoxic evaluation against the BT-549 breast cancer cell line revealed a half-maximal inhibitory concentration (IC50) of 6.401 μg/mL. These findings indicate that S. platensis-mediated silver-zinc oxide nanocomposites exhibit promising biological activity.

"Targeting Platelets in Breast Cancer: Insights into Pathophysiology and Therapeutic Strategies".

Microwave-assisted biosynthesis using marine Chlorella sp. extracts provides a green and efficient route for the production of silver nanoparticles (AgNPs). Compared with the conventional method (24 h), microwave-assisted synthesis reduces the reaction time to less than 7 min while producing smaller and more uniformly distributed nanoparticles. AgNPs were synthesized using extracts obtained with different solvents and directly compared with those produced via the conventional method to substantiate the efficiency of the microwave-assisted approach. UV–visible spectroscopy confirmed rapid nanoparticle formation, exhibiting surface plasmon resonance peaks in the range of 405 to 427 nm. TEM analysis revealed predominantly spherical AgNPs with particle sizes of approximately 10 to 20 nm. The XRD and FTIR analyses confirmed their crystalline structure and stabilization by algal-derived functional groups. The biological activities of the AgNPs were dependent on the extraction solvent. AgNPs synthesized using hexane extracts exhibited pronounced antibacterial activity, achieving minimum inhibitory concentrations as low as 0.31 µg/mL. In addition, the AgNP induced concentration-dependent cytotoxic effects in human breast cancer cell lines. IC50 values, determined via dose–response analysis, ranged from 0.18 to 0.67 μg/mL in MDA-MB-231 cells and 1.70 to 8.42 μg/mL in MCF-7 cells. These results indicate a potent cytotoxic profile, with MDA-MB-231 cells exhibiting significantly higher sensitivity to the microwave-assisted formulations. Collectively, these findings highlight microwave-assisted algal-mediated biosynthesis as a sustainable and effective platform for generating bioactive AgNPs with promising antibacterial and anticancer potential.

Metastasis remains a major challenge in cancer treatment due to the lack of effective targeted therapies. MBQ-167, a first-in-class dual Rac/Cdc42 inhibitor currently in a Phase 1 clinical trial, has demonstrated promising activity in preclinical breast cancer models by reducing tumor burden and preventing metastasis. To characterize its metabolism, we conducted liver microsome assays and identified several MBQ-167 metabolites. Of these, M6 was the primary metabolite from dog and human plasma following oral administration of MBQ-167. The M6 pharmacokinetics profile parallels that of MBQ-167 in human plasma from advanced breast cancer patients enrolled in the clinical trial. In metastatic breast cancer cell lines (HER2-BM, MDA-MB-231, MDA-MB-468), M6 exhibited minimal effects on cell viability and apoptosis, but strongly inhibited Rac1 activation without affecting Cdc42 activation. M6 also inhibited phosphorylation of Group 1 p21-activated kinases (PAKs) more effectively than MBQ-167 and significantly reduced breast cancer cell migration in wound healing and Transwell assays. In vivo studies with immunocompromised mice bearing HER2-BM tumors demonstrated that M6 inhibits tumor growth and metastasis to the lungs, livers, and kidneys by ~90%, comparable to MBQ-167. These findings suggest that M6 exhibits potent anticancer properties both in vitro and in vivo, potentially contributing to the sustained efficacy of MBQ-167 in metastatic breast cancer.

The efficacy of platinum(II) drugs, despite their wide use in clinical practice, is seriously limited by their well-known drawbacks. Octahedral Pt(IV) congeners are considered a sort of Holy Grail in cancer research as, being significantly more inert, they should be able to overcome the limitations of current platinum-based drugs, such as resistance and side effects, acting as prodrugs. Additionally, their anticancer activity can be tuned through a proper choice of the axial ligands released inside cancer cells when these compounds are reduced, making them even capable of potentially working as multiaction agents. However, despite their very satisfactory anticancer effects, no Pt(IV) complex has been approved for clinical use. As cell membrane permeation is the critical step, very poorly understood, of the whole mechanism of action of any drug, the investigation of the eventual differences in behavior between four-coordinate Pt(II) and six-coordinate Pt(IV) complexes when they diffuse in a lipid bilayer might be of significant relevance. The outcomes of a biased molecular dynamics (MD) investigation of the permeation of cisplatin and three simple cisplatin Pt(IV) derivatives through a membrane model prototype of human breast cancer cells are illustrated here. This comparative analysis of Pt(II) and Pt(IV) complex passive diffusion has been carried out with the aim of gaining indications about the factors that play a role in favoring or hindering membrane penetration and, ultimately, in determining the efficacy of their anticancer action.

Objective: This study aimed to analyze the chemical profiles of bioactive compounds in extracts from different parts of Clausena excavata (C. excavata), Millettia pachycarpa (M. pachycarpa), and Uvaria grandiflora (U. grandiflora), and to examine their antioxidant, anti-inflammatory, and cytotoxic effects on drug-sensitive and -resistant cancer and normal cells.Material and Methods: Ethyl acetate extracts from C. excavata fruits (FCE), M. pachycarpa roots and leaves (RMP and LMP), and U. grandiflora twigs and leaves (TUG and LUG) were analyzed for total phenolic and flavonoid content and the chemical profiles of bioactive compounds. Antioxidant activities were determined using various methods. Anti-inflammatory properties were investigated in lipopolysaccharide-stimulated RAW264.7 cells, and cytotoxicity was evaluated in doxorubicin-sensitive and -resistant leukemic cells (K562 and K562/adr), breast cancer cells (MCF-7 and MCF-7/adr), and normal cells (peripheral blood mononuclear cells; PBMCs). Results: The extracts contained bioactive compounds, including carbazole alkaloids, xanthones, and coumarins in FCE; isoflavonoids, coumarins, and rotenoids in RMP and LMP; and alkaloids, cyclohexenes, and flavonoids in TUG and LUG. TUG, RMP, and LMP exhibited the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, whereas RMP demonstrated the most potent 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and superoxide radical scavenging activities. LUG showed strong MCA, and LMP showed superior FRAP. FCE exhibited notable anti-inflammatory activity, whereas RMP showed significant cytotoxicity against MCF-7 and MCF-7/adr cells, with minimal toxicity to PBMCs. TUG also proved effective against drug-resistant leukemia cells.Conclusion: These findings highlight the potential of these plants for use in dietary supplements and cancer treatments, especially for drug-resistant cancers.

tRF-1432 orchestrates RBMS1-IMPDH2 regulatory control to drive purine-dependent chemoresistance in breast cancer.

Nebivolol-induced bi-directional modulation of intracellular kinases contributes to the inhibition of triple-negative breast cancer.

The spatiotemporal dynamics of protein kinase diffusion govern signal activation cascades, thereby modulating fundamental cellular functions. Pseudokinases, catalytically inactive members of the protein kinase superfamily, utilize noncatalytic signaling mechanisms to exert pivotal cellular functions and are frequently dysregulated in human diseases. While nanoscale dynamics of catalytically active receptors regulate signaling integrity, the functional significance of pseudokinase spatial organization remains unknown. Here, using aptamer-based single-molecule tracking in living cells, we observed heterogeneous diffusion modes of pseudokinase PTK7 (confined, Brownian, and directed motion). Specifically, spatially PTK7 diffusion coefficients (D) quantitatively correlate with metastatic potential across pancreatic, colorectal and breast cancer cell lines. Functional validation demonstrates that antibody-mediated PTK7 immobilization suppresses invasion, while Epithelial-Mesenchymal Transition (EMT) induction accelerates diffusion kinetics to promote metastasis. Crucially, faster PTK7 mobility increases stochastic collision frequency with tyrosine kinase-like orphan receptor 2 (ROR2), enhancing complex formation to robustly activate the WNT/PCP pathway. Moreover, in patient-derived primary cells, accelerated PTK7 kinetics positively correlate with invasive and metastatic phenotypes, confirming the clinical relevance of this biophysical regulatory mechanism. This work establishes pseudokinase spatial dynamics as a biophysical regulator of tumor progression, revealing a non-catalytic paradigm where receptor diffusion kinetics encode cellular behavior through stochastic signaling potentiation.

For double-strand breaks (DSBs) formed by radiation, onset of 5' to 3' end resection is a deciding factor in repair pathway choice, favoring homologous recombination (HR) over non-homologous end-joining (NHEJ). Studying HR-proficient MCF7 breast cancer cells, we confirmed a role for PARP1 in promoting DSB repair and limiting resection stress and identify the hexosamine biosynthetic pathway (HBP)-dependent post-translational modification O-GlcNAcylation as an independent regulator. Using pharmacological and genetic perturbations of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), we showed that O-GlcNAcylation can limit end resection as measured by BrdU and RPA staining, recruitment of HR proteins BRCA1 and RAD51, and accumulation of cytosolic DNA in S/G2-phase cells. These effects were independent of PARP1 but required the histone methyltransferase EZH2. Loss of OGT or EZH2 phenocopied PARP inhibition, leading to hyperresection after irradiation. The OGA inhibitor PUGNAc suppressed hyperresection due to PARP1 knockout while PARP inhibitor veliparib exacerbated defects in OGT- or EZH2-deficient cells. In each case, increased resection correlated with cytosolic DNA accumulation, suggesting a link to inflammatory signaling. These findings implicate the Warburg effect, via the HBP and O-GlcNAcylation, in favoring NHEJ over HR and suggest that disrupting EZH2 may sensitize HR-proficient tumor cells to radiation via resection-dependent mechanisms. Our results highlight the potential of targeting cancer-associated metabolic reprogramming to overwhelm HR repair and drive resection stress. Combining PARP inhibition with blockade of O-GlcNAcylation or EZH2 may offer a strategy to radiosensitize proliferating, HR-proficient cancers while sparing non-cycling normal tissues.

Bone metastasis remains a fatal and incurable condition for patients with breast cancer, leading to skeletal deterioration. The bone microenvironment enhances tumor proliferation and chemoresistance, necessitating novel therapeutic strategies. To investigate the cytotoxicity of two phytochemically-enriched plant extracts: Origanum vulgare (O.V.) and Vaccinium macrocarpon (V.M.) against breast cancer cells in a bone-metastatic condition. MCF-7 and MDA-MB-231 cell lines were treated with O.V. and V.M. for 24 h, in both 2D and 3D bone metastatic conditions. Live cell imaging, Alamar blue viability assay, RT-PCR, and flow cytometry analysis were used to assess cytotoxicity, apoptosis activation, and changes in oxidative stress/mitochondrial activity. Both extracts significantly inhibited cancer cell growth in a dose-dependent manner, with differential sensitivity observed between cell lines. Based on IC50 analysis, O.V. demonstrated greater efficacy against the bone metastatic MCF-7 cell line, while V.M. was more effective against the bone metastatic MDA-MB-231. Apoptosis activation was confirmed via upregulation of pro-apoptotic proteins p53 and caspase-9. Importantly, we observed that normal bone cells were unaffected by the treatments. These findings elucidate the promising yet untapped potential of O.V. and V.M. extracts as robust therapies for bone metastasis.

Background MRPS28 (Mitochondrial Ribosomal Protein S28) belongs to the MRP family and plays a critical role in mitochondrial translation and cellular energy metabolism. However, the effect of MRPS28 in pan-cancer remains unknown. This study aimed to perform a comprehensive assessment of the oncogenic potential of MRPS28 in pan-cancer using several databases, with a particular focus on breast cancer. Methods The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were employed to evaluate MRPS28 expression across pan-cancer. Furthermore, we analyzed the association between the expression of MRPS28 and diagnosis, prognosis, genetic alterations, genomic heterogeneity, DNA methylation, and immunity. In addition, the biological function of MRPS28 in breast cancer was investigated. The role of MRPS28 in the malignant biological behavior of breast cancer cells was studied through in vitro experiments, including cell proliferation, migration, and invasion. Results Our analyses indicated that MRPS28 expression dysregulation was noted in various cancer types, and MRPS28 had remarkable diagnostic and prognostic predictive values. MRPS28 expression was substantially related to genetic alterations, genomic heterogeneity, and DNA methylation levels. In addition, MRPS28 was associated with immune infiltration and immune-related gene expression in multiple cancer types. Moreover, our experimental validation confirmed that MRPS28 knockdown considerably suppressed proliferation, migration, and invasion, as well as promoted apoptosis in the breast cancer cell lines MDA-MB-231 and MCF-7. Conclusion Collectively, these findings imply that MRPS28 emerges as a potential diagnostic and prognostic biomarker across pan-cancer, with a potential oncogenic role in breast cancer progression. Furthermore, it may be a potential therapeutic target for various cancers.

Background/Objectives: To evaluate the diagnostic accuracy of two visual large language models (vLLMs), GPT-4o (OpenAI) and Claude Sonnet 3.5 (Anthropic), for detecting brain metastases in routine MRI using combined imaging and textual input. Methods: This retrospective study included 31 patients with and 46 without brain metastases with underlying melanoma (n = 24), lung cancer (n = 23), breast cancer (n = 17), or renal cell carcinoma (n = 13). In total, 100 MRI examinations (50 with, 50 without metastases) were provided to both vLLMs using a single representative slice per sequence, together with clinical history and the referring question. The generated free-text reports were evaluated for detection accuracy, overdiagnosis, correct sequence recognition, anatomical localization, lesion laterality, and lesion size estimation. Results: Both vLLMs showed perfect sensitivity (100% for both) but very low specificity (GPT-4o: 8%, Sonnet 3.5: 4%; p = 0.625), resulting in low diagnostic accuracy (GPT-4o: 54%, Sonnet 3.5: 52%; p = 0.625). Sequence identification was highly accurate in both models, with GPT-4o performing significantly better (100% vs. 93%; p < 0.05). Identification of the anatomical brain region (70% vs. 72%; p = 1.00) and lesion laterality (62% vs. 76%; p = 0.189) was comparable. Both models hallucinated additional lesions in 12% of cases. Lesion size measurements showed no significant differences between the models or in comparison with the radiologist. Conclusions: GPT-4o and Claude Sonnet 3.5 can generate radiological reports and detect brain metastases with excellent sensitivity, but their very low specificity, frequent hallucinations, and limited spatial reliability currently preclude clinical application. Future work should address how the balance between visual and textual input influences diagnostic behavior in vLLMs.

3α-Hydroxysteroid dehydrogenase type 3 (3α-HSD3) is a key steroid-metabolizing enzyme involved in the regulation of intratumoral androgen and estrogen levels, predominantly in estrogen receptor-positive (ER⁺) MCF-7 breast cancer cells. Its dysregulation influences proliferation, survival, and resistance to hormone-based therapy. The main goal of this study is to identify potential natural inhibitors of 3α-HSD3 from Terminalia arjuna phytoconstituents to modulate MCF-7 breast cancer cell proliferation. A panel of nine phytochemicals were evaluated through molecular docking, ADMET profiling, HOMO-LUMO energy gap analysis, and prediction of activity spectra for substances (PASS) to assess their drug-likeness and preliminary activity. Subsequently, molecular dynamics (MD) simulations were performed on top candidates to explore the structural stability and interaction dynamics of protein-ligand complexes. The selected compounds exhibited favorable docking scores against 3α-HSD3, with Luteolin(CMP1), Leucocyanidin(CMP2), Gallic Acid(CMP3), and Ellagic Acid(CPM4) forming stable hydrogen bonds with key active site residues. This study showed that the top four compounds may serve as potential 3α-HSD3 inhibitors of breast cancer, warranting further in vivo validation.

Ongoing efforts to investigate natural products with potential biological relevance continue to motivate research on medicinal plants. This study focused on isolating and characterizing secondary metabolites from the leaves of Piper porphyrophyllum collected in West Sumatra, and on evaluating the biological activity of the isolated compounds using both in vitro and in silico methods. The plant material was extracted, fractionated, and purified using chromatographic techniques, and mass spectrometry (MS), Ultraviolet (UV), infrared (IR), and nuclear magnetic resonance (NMR) spectroscopy were employed to establish the structure of the isolated compound. The cytotoxic activity was evaluated against MCF-7 breast cancer cells using the MTT assay, and molecular docking studies were performed with multiple proteins involved in breast cancer pathways. The investigation yielded 5,7-dimethoxyflavone, which showed cytotoxicity with an IC₅₀ of 9.94 μg/mL. Docking simulations suggested possible interactions with ERα, CDK4, CDK6, CDK2, and Bcl-xL, with binding scores of -7.8, -8.8, -8.8, -8.5, and -9.2 kcal/mol, respectively. The data suggests that 5,7-dimethoxyflavone is promising, and merits further examination for its relevance to breast cancer-related molecular targets.