Search Results (2,654)

Cyclin-Dependent Kinase 4/6 inhibitors (CDK 4/6i) represented a paradigm shift in the treatment of patients with metastatic hormone-receptor-positive (HR+), HER2-negative (HER2-) breast cancer patients. When disease progression occurs and further hormonal manipulations or target therapies fail, chemotherapy remains a therapeutic choice. For these reasons, resources should be invested in redesigning the best treatment strategy with the current chemotherapy drugs available. Nevertheless, the preferred strategy typically remains a planned sequence of single chemotherapeutic agents. This approach endeavors to extend overall survival and maintain quality of life. Within this complex and evolving therapeutic scenario, where the necessity for effective and treatment options is crucial, we explore in the present paper a perspective for a hypothetical new role of bevacizumab combined with paclitaxel for patients with metastatic HR+, HER2- breast cancer patients resistant to hormone therapy. Recent findings from our preliminary published pharmacogenetic studies, could suggest the efficacy of bevacizumab as linked to a well-defined genomic profile of genes implicated in the process of neoangiogenesis (e.g., favorable profile: VEGF-A rs833061/VEGFR-2 rs1870377: CT/AT, CT/AA, TT/AA, TT/TT, CC/TT), concluding the present perspective underlying the fact that bevacizumab combined with paclitaxel will be reconsidered with this new potential use only if well-designed prospective trials confirm what has been observed from our retrospective data. Full article

Breast cancer treatment still faces challenges including local recurrence, systemic toxicity, tumor heterogeneity, drug resistance, and immunosuppression. Conventional systemic administration provides limited exposure at the tumor site and exhibits significant toxicity. Injectable hydrogels, combining the properties of minimally invasive administration, in situ gelation, local retention, and sustained release, have become a key platform for local precision drug delivery. Compared with nanomedicines or free drugs, hydrogels can both prolong drug retention time and achieve on-demand release through the modulation of crosslinking density, degradation rate, and responsive chemical bonds. This review is organized around the material logic of such systems. Injectable hydrogels are first classified into natural, synthetic, hybrid, supramolecular, nanocomposite, and self-healing systems, the in situ gelation chemistries available to each are compared, and network parameters such as crosslinking density, mesh size, swelling, porosity, modulus, and rheology are related to release kinetics and intratumoral retention. Current research is primarily advancing along two directions: one is the construction of pH-, enzyme-, redox/ROS-, hypoxia-, ATP-, glucose-or thermo-responsive hydrogels; the other is achieving active targeting by integrating functionalized hydrogels with targets such as CD44, folate receptor, integrins, EGFR, transferrin receptor, and HER2 or with biomimetic cell-membrane coatings. On this basis, hydrogels have been extended to cancer vaccines, immune checkpoint modulation, local delivery of CAR-T/CAR-NK, as well as combination therapies involving chemotherapy, photothermal therapy, photodynamic therapy, chemodynamic therapy, sonodynamic therapy, radiosensitization, gene therapy, and theranostics. The constraints imposed on hydrogel design by different payload classes, including small molecules, natural products, proteins and peptides, nucleic acids, antibodies, exosomes, and gene-editing machinery, are further examined, and imaging-integrated theranostic gels are discussed together with the emerging role of machine learning and digital fabrication in hydrogel optimization. Based on the biological foundations of breast cancer, this review summarizes advances in the material design, microenvironment-responsive release, targeting strategies, immunomodulation, and combination therapy of hydrogels, critically evaluates the limitations of each strategy, and aims to provide a reference for the design of mechanistically well-defined and translatable hydrogel delivery systems for breast cancer. Full article

Breast cancer (BC) is the most frequently diagnosed malignancy and generally the leading cause of cancer-related mortality among women worldwide. Molecular targeted therapies, including endocrine treatment for hormone-responsive tumors, anti-HER2 agents for HER2-positive tumors and PARP inhibitors (PARPis) for homologous recombination-deficient (HRD) tumors, have significantly improved patient outcomes, but several clinical challenges are still open. The development of acquired resistance strongly limits the long-term efficacy of current treatment strategies, underscoring the necessity to identify novel therapeutic approaches for breast cancer therapy. In this review, we summarize and discuss recently investigated natural compounds with anti-breast cancer activity, ranging from polyphenols, terpenoids, alkaloids, sulfur-containing compounds and the emerging plant-derived extracellular vesicles. We focus on their ability to induce DNA damage or oxidative stress, modulating the DNA damage response (DDR) and interfering with key oncogenic signaling pathways. We also discuss the potential of these compounds to enhance the efficacy of conventional therapies, thereby offering a promising role in overcoming clinical resistance. Despite clinical relevance remains under development and further studies are required; many of the natural compounds examined here appear to effectively target DDR signaling and oncogenic pathways, supporting their potential use in breast cancer therapy. Full article

Breast cancer remains a leading cause of cancer-related mortality worldwide, highlighting the need for novel therapeutic strategies that selectively target tumor cells while minimizing systemic toxicity. Dietary ammonium hydroxide enhancement (AHE) has previously been shown to modulate metabolic pathways in animal studies. However, its potential as a localized anticancer therapy has not been investigated. In the present study, we evaluated the antitumor efficacy and systemic safety of NH₄OH using complementary in vitro and orthotopic breast cancer xenograft models. MDA-MB-231 breast cancer cells and non-tumorigenic MCF10A mammary epithelial cells were treated with increasing concentrations of NH₄OH (2.5–225 µM) to assess dose-dependent effects on cell proliferation, viability, and apoptosis. Following this, MDA-MB-231 cells were orthotopically xenografted into female athymic nude mice and treated by intratumoral injection with NH₄OH using a stepwise dose-escalation regimen (0.01%, 0.1%, and 0.5%; total volume of 20 μL per tumor divided between two injection sites) or phosphate-buffered saline (PBS). Differences between treatment groups of mammary tumors and kidney tissues were analyzed molecularly and histologically. NH₄OH significantly suppressed MDA-MB-231 cell growth and metabolic activity, with minimal effects on MCF10A cells, and induced apoptosis in MDA-MB-231 cells without detectable apoptotic induction in MCF10A cells. In vivo, although tumor volume only showed a non-significant downward trend, histological and molecular analyses demonstrated substantial alterations in tumor biology. NH₄OH treatment induced molecular changes consistent with an antitumor response, including increased Caspase-3 and p53 expression, reduced BCL2 and Ki-67 expression, and attenuation of TNFα, IL-6, and TLR4 inflammatory signaling. Furthermore, the tumor architecture in T-NH tumors displayed increased pale eosinophilic regions and reduced cellular density, suggestive of treatment-associated tumor tissue disruption. Histological analysis of kidney tissue showed no evidence of overt renal toxicity. Indeed, localized NH₄OH administration was associated with reduced renal inflammatory and apoptotic signaling, preserved renal morphology, and increased expression of the ammonia transporters RHBG and RHCG. Cross-sectional morphometric measurements showed decreased area for the distal convoluted tubules in NH₄OH-treated samples. Although this initial preclinical study was limited by a relatively small sample size, further studies are warranted to validate these findings and define the molecular mechanisms underlying NH₄OH-mediated antitumor activity. Collectively, these findings suggest that intratumoral NH₄OH modulates tumor metabolic, inflammatory, and apoptotic pathways associated with a less aggressive tumor phenotype while showing no overt molecular or histological evidence of renal injury, supporting further investigation as a localized metabolic intervention targeting molecular and histological drivers of breast cancer progression. Full article

Breast cancer remains one of the most common malignancies worldwide. Highly invasive HER2-positive breast cancer carries a high risk of metastasis and poses a significant therapeutic challenge. Boron neutron capture therapy (BNCT) may be an option for patients with this severe diagnosis. Here we evaluated the effectiveness of BNCT with elemental boron nanoparticles obtained by laser fragmentation and coated Silane-PEG-COOH and conjugated with the Affibody _ZHER2:342 guide protein (BPs) against the HER2-positive breast cancer. The MTT assay after BNCT with BPs revealed an almost twofold reduction in surviving BT-474 tumor cells compared to the control group. The results of the clonogenic test showed totally death of BT-474 cells after BNCT with BPs at a concentration of 40 μg/mL in the culture medium. The same results was found for in vivo. In female SCID mice bearing BT-474 breast tumor xenografts, BNCT with intratumoral injection of BPs at a dose of 60 mg/kg led to a significant slowdown in xenograft growth beginning on the 17th day compared with control animals and the 39th day compared with irradiated females. A single intratumoral administration of BPs at a dose of 60 mg/kg did not show toxic effects. Histological examinations did not reveal systemic accumulation of the studied BPs in major organs; instead BPs was selectively retained within the xenografts and surrounding tissues. Thus, laser fragmented functionalized with Silane-PEG-COOH and the Affibody _ZHER2:342 (BPs B-PEG-AFF) represent a promising platform for boron delivery in targeted BNCT applications. Full article

Triple negative breast cancer (TNBC) continues to have a poor prognosis relative to other forms of this disease. Previous studies have shown that the HOX family of transcription factors generally show increased expression in breast cancer and may have a primarily pro-oncogenic role. In this study, we assessed the sensitivity of a range of TNBC-derived cell lines to an inhibitor of HOX protein function, HTL-001, which blocks the interaction between HOX proteins and the Pre-B-cell Leukaemia Homeobox (PBX) cofactor. The sensitivity of cell lines was measured by MTS viability assays, and gene expression by RT-qPCR. Combination studies were performed with epigenetic modifiers (5-azacytidine (5-aza), Trichostatin A (TSA)) and standard-of-care chemotherapeutic drugs including Paclitaxel. A mouse tumour flank model of MDA-MB-231 cells was used to assess response to HTL-001, paclitaxel, or combination therapy. All the cell lines exhibited high levels of HOX dysregulation compared to an immortalised line derived from normal breast cells, and greater sensitivity to HTL-001-induced apoptosis. Epigenetic changes have previously been shown to be key modulators of HOX expression and, correspondingly, we show that reversing epigenetic changes in these cell lines significantly alters HOX expression and generally reduces sensitivity to HTL-001. In addition, HTL-001 shows synergistic interactions with several established chemotherapeutic agents in vitro. We further demonstrate that HTL-001 can significantly reduce tumour growth in a mouse model of TNBC. Our findings indicate that HOX/PBX dimers are a potential therapeutic target in this cancer. Full article

Breast cancer, especially triple-negative breast cancer (TNBC) and endocrine-resistant disease, remains difficult to treat because of limited effective targeted therapies. In this study, we evaluated the antitumor activity and potential mechanism of MHO7, a marine-derived ophiobolin metabolite, in ER-positive ZR-75-30 cells, tamoxifen-resistant LCC2 cells, and TNBC MDA-MB-231 models. MHO7 dose-dependently reduced cell viability, wound closure, and clonogenic growth in ZR-75-30 and LCC2 cells, with IC₅₀ values of 11.53 and 10.43 μM, respectively. MHO7 also promoted apoptotic cell death, accompanied by increased reactive oxygen species accumulation and altered expression of apoptosis-related proteins, including Bcl-2 and caspase-3. N-acetyl-L-cysteine partially attenuated MHO7-induced apoptosis and YAP reduction in MDA-MB-231 cells, suggesting a contribution of oxidative stress. Molecular docking predicted that MHO7 could occupy the conserved TEAD palmitoylation pocket, and subsequent in vitro analyses showed suppression of YAP/TAZ-TEAD signaling, including reduced YAP nuclear accumulation and decreased TEAD4 expression. In an MDA-MB-231 xenograft model, MHO7 significantly inhibited tumor growth, reduced CD31-positive microvessel density, and decreased Hippo pathway-related transcriptional readouts. These findings indicate that MHO7 exerts broad antitumor activity in breast cancer models through oxidative stress-associated apoptosis and modulation of YAP/TAZ-TEAD signaling, supporting its further development as a lead compound for treatment-resistant breast cancer. Full article

Background: Increasing resistance against protein kinase inhibitors used in cancer therapies enforces the search for novel target structures to be addressed with favourable small-molecule inhibitors. One of these novel target structures is the tyrosine kinase Brk that is known to play a prominent role in breast cancer progression. Moreover, Brk overexpression in various kinds of cancer is associated with poor outcomes, making Brk an interesting target structure for potential treatment. So far, no class of promising Brk inhibitors has been identified. Methods: We synthesized novel functionalized pyrrolopyridines in one- and two-step reactions under substitution of the molecular scaffold and the 4-aniline residue, respectively. They were evaluated as inhibitors of Brk and HER2 in a radiolabelled enzyme assay. Results: The most favourable substituents for Brk inhibitory activity at the aniline residues were 3-hydroxy functions combined with either bromo or nitro substituents at the molecular scaffold. Those compounds, as well as bromo- and nitro-substituted compounds, also showed the best HER2 inhibitor activities. Conclusions: Novel pyrrolopyridines were discovered to be a promising class of nanomolar Brk inhibitor with additional HER2 activities to further strengthen Brk inhibitory activity in prospective anticancer therapies. Thus, the first class of Brk inhibitors could be identified. Full article

Cancer remains a leading global cause of morbidity and mortality, with oxidative stress playing a central role in its pathogenesis, progression, and response to therapy. Nutrition has emerged as a modifiable factor capable of influencing redox homeostasis, thereby contributing to both cancer prevention and therapeutic outcomes. This narrative review summarizes current evidence on dietary patterns, specific nutrients, and bioactive compounds that modulate oxidative stress and are associated with reduced cancer risk and improved response to treatment. A literature search was conducted using PubMed, Scopus, and Google Scholar, covering the period from 2002 to 2025 to capture contemporary dietary approaches and clinical evidence. Eligible studies addressed nutrient compounds, dietary strategies, obesity, gut microbiota, conventional cancer therapies, and clinical outcomes, with particular emphasis on mechanisms related to oxidative stress, inflammation, and immune modulation. Epidemiological evidence consistently supports the protective role of plant-based dietary patterns and reduced intake of red and processed meat, partly due to their antioxidant and anti-inflammatory properties. Nutrients such as dietary fiber, polyphenols, and omega-3 fatty acids are associated with decreased oxidative damage, improved immune responses, and enhanced therapeutic efficacy across multiple tumor types, including colorectal, breast, lung, and ovarian cancers, as well as glioblastoma. Emerging data also suggest that dietary interventions, including ketogenic diets and fasting, may influence tumor metabolism and redox balance, potentially increasing sensitivity to conventional therapies. The gut microbiota has been identified as a key mediator linking diet, oxidative stress, and cancer-related pathways. Although current evidence supports the role of nutritional strategies in targeting oxidative stress for cancer prevention and treatment, further large-scale randomized clinical trials are required to clarify their impact on survival and treatment efficacy. The integration of nutritional counseling into oncology practice represents a cost-effective, accessible, and patient-centered approach with the potential to modulate oxidative stress and improve clinical outcomes. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. The molecular drivers of its progression and metabolic reprogramming remain unclear. Here, we identify cell division cycle-associated 4 (CDCA4) as a novel oncogenic driver in TNBC. Analysis of the TCGA-BRCA dataset, including 1085 breast cancer tissues and 112 normal tissues, showed that CDCA4 expression was significantly upregulated in breast cancer tissues. Subgroup analysis of TCGA-BRCA samples further showed higher CDCA4 expression (fold change = 1.707) in TNBC than in non-TNBC samples [TNBC, n = 116; non-TNBC, n = 984]. Survival analysis demonstrated that high CDCA4 expression was associated with poorer overall survival, with a hazard ratio of 1.54 (log-rank p = 0.0053). Functional assays demonstrated that CDCA4 knockdown suppresses proliferation, migration, invasion, and tumor growth in vitro and in vivo, whereas overexpression exerts opposite effects. RNA-sequencing revealed that CDCA4-regulated genes are enriched in lipid metabolism and mTOR signaling pathways. Mechanistically, CDCA4 depletion reduces intracellular lipids and the expression of lipogenic enzymes (FASN, ACC1). We show that CDCA4 activates mTOR and increases the nuclear active form of SREBP1, enhancing its promoter occupancy. Pharmacological mTOR inhibition reverses CDCA4-induced malignancy and metabolic alterations. Furthermore, Our findings suggest that SESN2 may contribute to CDCA4-mediated activation of mTOR signalling. SESN2 knockdown attenuates mTOR signaling and negates the pro-tumorigenic effects of CDCA4 overexpression. Collectively, these findings demonstrate that CDCA4 drives TNBC progression and lipid reprogramming via the SESN2/mTOR/SREBP1 axis, positioning CDCA4 as a potential prognostic biomarker and therapeutic target. Full article

Breast cancer is among the most common cancers globally. While several advancements have been made to improve breast cancer management, there is still a need to find innovative ways to deliver drug therapy to improve efficacy and side effects associated with treatment. Among these methods, local and targeted drug delivery is particularly promising. The current review highlights localized polymer-based methods to effectively deliver breast cancer therapy, with a specific focus on the strengths and limitations of these systems. Injectable and surgically implanted scaffolds, microneedles, topical patches, liquid and semisolid topical drug carriers are amongst some of the delivery systems discussed. Highlighted in the discussion is how physiological changes that occur during breast cancer should be considered and utilized when developing drug formulations, by specifically exploiting the tumor microenvironment. Remaining gaps and future areas for drug delivery research are highlighted including personalized medicine and insights into novel drug delivery systems like nanomedicines and three-dimensional drug printing. Full article

Background: Chronic psychological stress drives metastasis in triple-negative breast cancer (TNBC), yet the underlying mechanisms remain poorly understood and effective interventions are lacking. Stress-induced expansion of myeloid-derived suppressor cells (MDSCs) and subsequent immune remodeling play critical roles, with aberrant myeloid differentiation of hematopoietic stem and progenitor cells (HSPCs) serving as a major source of MDSCs. This study investigates whether epicatechin gallate (ECG) suppresses stress-driven TNBC growth and lung metastasis by regulating HSPC myeloid differentiation. Methods: A mouse model of chronic unpredictable mild stress (CUMS) followed by 4T1 tumor implantation was used to evaluate the anti-tumor effects of ECG. CETSA-WB, molecular docking, HSPC differentiation assays, and MDSC functional validation assays, along with immunohistochemistry, immunofluorescence, and flow cytometry, were performed to elucidate how ECG modulates glucocorticoid (GC)/glucocorticoid receptor (GR) signaling and HSPC differentiation. Results: ECG dose-dependently alleviated depressive-like behaviors, reduced serum corticosterone (Cort), and inhibited tumor growth and lung metastasis. Notably, ECG decreased lung metastatic foci by 76.9% relative to the CUMS group. Mechanistically, chronic stress activated GR and induced its nuclear translocation in HSPCs, promoting aberrant HSPC-to-MDSC differentiation. ECG directly bound GR, blocked its nuclear translocation, and suppressed the myeloid differentiation of HSPCs into MDSCs, which was accompanied by downregulation of S100A8/A9, fibronectin, and MMP-2, as well as increased CD8⁺ T cell infiltration. Supernatants from ECG-pretreated and differentiated HSPCs reversed Cort-induced epithelial–mesenchymal transition (EMT) in 4T1 cells. Conclusions: ECG acts as a natural GR signaling blocker that directly targets GR to block chronic stress-driven abnormal myeloid differentiation of HSPCs, thereby remodeling the pulmonary immune microenvironment, suppressing EMT, and reducing breast cancer lung metastasis. These findings identify ECG as a promising GR signaling blocker and a potential adjuvant therapy for cancer patients under high-stress conditions. Full article

Background. Breast and ovarian cancer are among the most common neoplasms in women, and germline variants in the BRCA1 gene markedly increase the risk of developing them. Despite existing studies, the frequency and spectrum of BRCA1 variants in women from Jalisco, Mexico, remain underexplored. Objective. To identify and characterize BRCA1 variants in a cohort of Mexican women with breast and ovarian cancer, and to assess their functional and splicing consequences through computational analysis. Methodology. Genomic DNA from 228 women with breast and/or ovarian cancer, selected by clinical criteria suggestive of hereditary cancer, was analyzed by next-generation sequencing. The functional impact of point variants was predicted with Ensembl VEP, SIFT, PolyPhen-2, REVEL, CADD, and AlphaMissense, and their effect on splicing was evaluated with SpliceAI, using the MANE Select canonical transcript (NM_007294.4). Results. BRCA1 variants were identified in 14.0% of this screening-enriched cohort, with carrier proportions of 16.2% in ovarian and 13.6% in breast cancer; these figures reflect a selected series and do not represent population prevalence. Breast cancer carriers showed a younger age at diagnosis, a higher proportion of the triple-negative phenotype, and a stronger family history. Fourteen-point variants and four large rearrangements were detected, with a predominance of truncating loss-of-function alterations. The recurrent missense variant c.5123C>A (p.Ala1708Glu), located in the BRCT1 domain, was the most relevant finding, present in 28.1% of carriers (9/32). The computational analysis did not reclassify variants on its own but provided complementary evidence (PP3/BP4) consistent with current classifications: it allowed reannotation of c.5243G>A from nonsense to missense, supported the pathogenic nature of the intronic splice variant c.4987-3C>A, and was concordant with the likely benign interpretation of c.2735A>G, while c.3367G>T remained of uncertain significance. Conclusions. This cohort from Western Mexico harbors a distinctive spectrum of BRCA1 variants, including the recurrent c.5123C>A variant, which may reflect a regional founder effect warranting haplotype analysis. These findings underscore the need for local evidence and for genetic panels adapted to the Mexican population, to enable accurate and equitable variant interpretation and access to targeted therapies such as PARP inhibitors. Full article

Despite the development of new drugs, chemoresistance constitutes a major obstacle in cancer treatment. To investigate mechanisms of resistance and potential therapeutic targets, we developed doxorubicin-resistant models of HER2− (D2F2/Dox) and HER2+ (D2F2E2/Dox) breast cancer cells. Compared with parental cells, the D2F2/Dox and D2F2E2/Dox differed in morphology, increased migratory potential, elevated levels of the transcription factor signal transducer and activator of transcription 3 (Stat3), and a lower proliferation rate in D2F2E2/Dox. Moreover, D2F2/Dox and D2F2E2/Dox differed in the expression profiles of genes related to cell stemness, apoptosis, and drug efflux. Stat3 gene silencing in both doxorubicin-resistant cell types reversed the expression profiles of some genes (different in each resistant cell line), and decreased migratory potential was observed only in D2F2 cells. These data indicate that the acquired doxorubicin resistance was associated with Stat3 status; however, HER2− and HER2+ breast cancer cells did not indicate the same mechanism of chemoresistance acquisition. Importantly, Stat3 silencing did not substantially restore doxorubicin sensitivity, suggesting that effective therapy may require simultaneous targeting of multiple pathways. Furthermore, we demonstrated that siStat3 therapeutics could be selectively delivered to HER2+ cancer cells using H2.1MS1:MS2KN silk spheres, indicating their potential for targeted drug delivery in vivo. Full article

Human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (Trop-2) are tumor-associated antigens widely overexpressed in multiple malignant tumors, which drive malignant proliferation, invasion, metastasis, and therapeutic resistance by activating key downstream signaling pathways. Antibody–drug conjugates (ADCs) targeting HER2 and Trop-2 leverage their antigen-specific binding capacity to achieve precise targeted delivery of cytotoxic drugs, representing a significant breakthrough in solid tumor therapy. This review systematically outlines the biological functions and carcinogenic mechanisms of HER2 and Trop-2, focusing on the latest research and development progress of related ADCs. We also summarize and analyze key clinical data and application prospects in breast cancer (BC), gastric cancer (GC), non-small cell lung cancer (NSCLC), and urothelial carcinoma (UC), while also delving into the challenges and future directions within this field. Full article