Search Results (234)

Chemoresistance is a major challenge in the treatment of triple-negative breast cancer (TNBC). Multicellular spheroids are an attractive platform for investigating chemoresistance in TNBC, as they replicate the cues of the tumour microenvironment in vivo. We conducted a comprehensive literature search to summarise the multifactorial and interlinked mechanisms driving chemoresistance in TNBC spheroids. These mechanisms include spatial heterogeneity, hypoxia, extracellular matrix remodelling, tumour–stroma crosstalk, drug efflux, apoptotic resistance, and cancer stem cell signalling. Strategies for overcoming chemoresistance in TNBC spheroids include nanocarrier systems to overcome spatial diffusion limitations, pathway inhibition, and targeting tumour–microenvironment interactions. Despite their advantages, some spheroid models face challenges such as low reproducibility, a lack of heterogeneity, variability in size and shape, limited vascularisation, and constraints in long-term culture. Advanced culturing platforms such as clinostat bioreactors allow for extended culture periods, enabling mature spheroid drug testing. Furthermore, advanced analytical techniques provide spatially resolved spheroid data. These multifactorial and interlinked mechanisms reflect the tumour microenvironment in vivo that spheroids recapitulate, rendering them valuable models for studying chemoresistance. The incorporation of stromal components and advanced analytical workflows will enhance the utility and translational relevance of spheroids as reliable preclinical models for drug discovery in TNBC. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Background/Objectives: Truncating mutations in PALB2, a critical component of the BRCA1-PALB2-BRCA2 homologous recombination repair complex, are associated with increased risk and aggressiveness of breast cancer. The consequences of PALB2 truncation on the expression, localization, and functional dynamics of the scaffold protein IQGAP1 were investigated in this study based on two cases of truncated PALB2 human breast invasive ductal carcinoma (IDC), specifically, c.1240C>T (p.Arg414*) and c.2257C>T (p.Arg753*). Methods: Using confocal microscopy, we examined co-expression patterns of IQGAP1 with PALB2, PCNA, CK7, and β-tubulin in tumor tissues from both control cancer and PALB2-mutated cases. Results: In PALB2-truncated tumors, IQGAP1 exhibited enhanced peripheral and plasma membrane localization with elevated co-localization levels compared to controls, suggesting altered cytoskeletal organization. PALB2 truncation increased nuclear and cytoplasmic N-terminal PALB2 immunoreactivity, indicating the presence of truncated isoforms disrupting the homologous recombination repair system. Co-expression analyses with PCNA revealed an inverse expression pattern between IQGAP1 and proliferation markers, suggesting S-phase cell cycle-dependent heterogeneity. Furthermore, the loss of IQGAP1 dominance over CK7 and β-tubulin in mutant tumors, along with persistent intercellular spacing, implied a loss of cell–cell cohesion and the acquisition of invasive traits. Conclusions: These data support a model where PALB2 truncation triggers a reorganization of IQGAP1 that disrupts its canonical structural functions and facilitates tumor progression via enhanced motility and impaired cell–cell interaction. IQGAP1 thus serves as both a functional effector and potential biomarker in PALB2-mutated IDC, opening novel paths for diagnosis and targeted therapeutic intervention. Full article

The tumor microenvironment (TME) plays a central role in cancer progression, with tumor-associated macrophages (TAMs) and extracellular matrix (ECM) components such as collagen being key modulators of invasiveness and immune regulation. Although macrophage infiltration and ECM remodeling are well-documented individually, their coordinated contribution to mammary carcinoma aggressiveness remains underexplored, particularly in comparative oncology models. This study analyzed 117 mammary carcinoma samples—59 from dogs and 58 from women—using immunohistochemistry, immunofluorescence, and second-harmonic-generation (SHG) microscopy. We quantified TAM density and phenotype (CD206, iNOS, and S100A8/A9), assessed collagen fiber organization, and examined correlations with clinical–pathological variables and overall survival. Increased TAM infiltration was associated with a higher histological grade, aggressive molecular subtypes, enhanced cell proliferation, and shortened survival in dogs. High TAM density also correlated with decreased collagen fiber length and increased alignment, suggesting active immune–matrix remodeling in aggressive tumors. Macrophage phenotyping revealed heterogeneous populations, with CD206⁺ cells predominating in high-grade tumors, while S100A8/A9⁺/iNOS⁺ phenotypes were enriched in less aggressive subtypes. The findings were consistent across species, reinforcing the relevance of canine models. Our results identify macrophage–collagen interactions as critical determinants of tumor aggressiveness in mammary carcinomas. This study bridges comparative oncology and translational research by proposing immune–ECM signatures as potential prognostic biomarkers and therapeutic targets. These insights contribute to the advancement of molecular oncology in Brazil by supporting innovative strategies that integrate immune modulation and matrix-targeted interventions in breast cancer. Full article

Plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) is a novel epigenetic “reader” that specifically recognises histone post-translational modifications (PTMs) via its Tudor and PHD finger domains, thereby regulating chromatin remodelling, DNA damage repair, and oncogene transcriptional activation. This review comprehensively summarises the role of PHF20L1 in various cancers, including breast, ovarian, and colorectal cancers, as well as retinoblastomas, and elucidates its molecular mechanisms of action in cancer pathogenesis. Accumulating evidence indicates that PHF20L1 is upregulated in these malignancies and drives tumour progression by promoting proliferation, metastasis, and immune evasion. Furthermore, PHF20L1 orchestrates tumour-related gene expression by interacting with key epigenetic complexes. Given its unique structural features, we propose novel strategies for developing small-molecule inhibitors and combinatorial therapies, providing a theoretical basis for targeted epigenetic regulation for precision treatment. Future research should further investigate the molecular regulatory networks of PHF20L1 in different cancers and other human diseases and focus on developing specific small-molecule inhibitors to enable precision-targeted therapies. Full article

Plants produce an extensive repertoire of secondary metabolites, developed over evolutionary time to support survival. Among these, D-limonene, a monoterpene exuded by citrus fruits, has demonstrated a broad range of pharmacological activities. This review elucidates limonene’s biological versatility, spanning antioxidant, anti-inflammatory, antitumor, antidiabetic, neuroprotective, and gastroprotective domains. Synthesizing data from both preclinical and early-phase clinical research, we explore its molecular mechanisms, ranging from reactive oxygen species mitigation and apoptosis induction to metabolic remodeling and neurotransmitter modulation. Special attention is given to limonene’s emerging role in oncological therapeutics, notably in breast and liver cancers, and its capacity to ameliorate pathophysiological hallmarks of diabetes and neurodegeneration. Its low toxicity and high bioavailability support its potential as a safe adjunct or alternative in phytotherapy. This review advocates for continued investigation into limonene’s translational potential across a spectrum of neoplastic and non-neoplastic diseases. Full article

Pre-metastatic niche (PMN) formation is a critical step in metastatic progression. However, the biological effects of subtherapeutic doses of ionizing radiation (SDIRs) following radiotherapy on this process remain unclear. Using a 4T1 breast cancer mouse model, we investigated the effects of SDIRs (3 × 0.3 Gy) on lung PMN development and metastasis upon SDIR exposure on days 8–10 post-tumor injection, followed by mastectomy and analyzed on day 24. SDIRs significantly increased the total metastatic volume (TMV) in lungs, suggesting an accelerated PMN formation. Mechanistically, the SDIR acted as an early catalyst for niche priming, upregulating Bv8 expression, enhancing neutrophil recruitment, and increasing MMP9, S100A8, and Il6 production in the PMN by day 11. Moreover, SDIR drives metastasis through distinct mechanisms. Proteomic analysis revealed SDIR-driven metabolic reprogramming, with a shift away from fatty acid metabolism toward glycolysis and lipid accumulation within the PMN. This shift contributes to extracellular matrix (ECM) remodeling, immune modulation, and the upregulation of adhesion-related pathways, shaping a microenvironment that accelerates metastatic outgrowth. By reprogramming the pre-metastatic lung, the SDIR highlights the need to integrate organ-specific radiation exposure into metastasis models. Metabolic and immune-stromal pathways emerge as potential therapeutic targets, underscoring the importance of refining radiotherapy strategies to mitigate unintended pro-metastatic effects. Full article

Breast cancer metastasis remains the primary driver of patient mortality, involving dynamic interactions between tumor cells and distant organ microenvironments. In recent years, tumor cell-derived extracellular vesicles (EVs) have emerged as critical information carriers, playing central roles in breast cancer metastasis by mediating organ-specific pre-metastatic niche formation, immune modulation, and tumor cell adaptive evolution. Studies have demonstrated that EVs drive the metastatic cascade through the delivery of bioactive components, including nucleic acids (e.g., miRNAs, circRNAs), proteins (e.g., integrins, metabolic enzymes), and lipids, which collectively regulate osteoclast activation, immune cell polarization, vascular permeability alterations, and extracellular matrix (ECM) remodeling in target organs such as bone, the lungs, and the liver. Molecular heterogeneity in EVs derived from different breast cancer subtypes strongly correlates with organotropism, providing potential biomarkers for metastasis prediction. Leveraging the organotrophic mechanisms of EVs and their dual regulatory roles in metastasis (pro-metastatic and anti-metastatic), strategies targeting EV biogenesis, cargo loading, or delivery exhibits translational potential in diagnostics and therapeutics. In this review, we summarize recent advances in understanding the role of breast cancer-derived exosomes in mediating metastatic organotropism and discuss the potential clinical applications of targeting exosomes as novel diagnostic and therapeutic strategies for breast cancer. Full article

The extracellular matrix (ECM) provides structural support to cells, thereby forming a functional tissue. In cancer, the growth of the tumor creates internal mechanical stress, which, together with the remodeling activity of tumor cells and fibroblasts, alters the ECM structure, leading to an increased stiffness of the pathological ECM. The enhanced ECM stiffness, in turn, stimulates tumor growth and activates tumor-promoting fibroblasts and tumor cell migration, leading to metastasis and increased therapy resistance. While the relationship between matrix stiffness and migration has been studied before, their connection to internal tumor stress remains unresolved. Here we used 3D ECM-embedded spheroids and hydrogel particle stress sensors to quantify and correlate internal tumor spheroid pressure, ECM stiffness, ECM remodeling, and tumor cell migration. We note that 4T1 breast cancer spheroids and SV80 fibroblast spheroids showed increased invasion—described by area, complexity, number of branches, and branch area—in a stiffer, cross-linked ECM. On the other hand, changing ECM stiffness only minimally changed the radial alignment of fibers but highly changed the amount of fibers. For both cell types, the pressure measured in spheroids gradually decreased as the distance into the ECM increased. For 4T1 spheroids, increased ECM stiffness resulted in a further reach of mechanical stress into the ECM, which, together with the invasive phenotype, was reduced by inhibition of ROCK-mediated contractility. By contrast, such correlation between ECM stiffness and stress-reach was not observed for SV80 spheroids. Our findings connect ECM stiffness with tumor invasion, ECM remodeling, and the reach of tumor-induced mechanical stress into the ECM. Such mechanical connections between tumor and ECM are expected to drive early steps in cancer metastasis. Full article

Targeting and multidrug resistance are the significant problems of current antitumor drugs, and these problems become the key factors in the design of nanomedicine. Herein, Au NRs and OPC-Au NPs were prepared via the hydroquinone seedless growth method and proanthocyanidin (OPC) one-pot method, and then pH-GSH-near-infrared ΙΙ (NIR-ΙΙ)-responsive nano-prodrugs Au/DOX-ss LNRs and OPC-Au/DOX-ss LNPs were designed by the encapsulation of doxorubicin prodrug DOX-ss with Au-S affinity and thermal-sensitive liposomes. Interestingly, OPC endowed OPC-Au NPs with reducibility and excellent performance in terms of particle size, zeta potential, encapsulation rate, and drug loading rate. In particular, the photothermal efficiencies of OPC-Au/DOX-ss LNPs increased to 59.22% under the 1064 nm NIR-ΙΙ irradiation. Compared with free DOX-ss and Lipid DOX-ss, the IC50 of OPC-Au/DOX-ss LNPs was decreased by 91.68% and 97.60%, respectively. Furthermore, the expression of P-gp in MCF-7/ADR was significantly inhibited (decreased by 65%). The potential of proanthocyanidin remodels the pH-GSH-NIR-ΙΙ responsiveness and drug resistance of OPC-Au/DOX-ss LNPs for breast cancer treatment in NIR-ΙΙ photodynamic/photothermal therapy. Full article

Triple-negative breast cancer (TNBC) is an aggressive cancer characterized by a high risk of recurrence, invasiveness, metastatic potential, and poor prognosis. Tumor-associated macrophages (TAMs), particularly M2-like TAMs, contribute to TNBC progression by promoting an immunosuppressive tumor microenvironment (TME), highlighting the need for TME remodeling. This study aimed to evaluate the therapeutic efficacy of co-administering CL7, a CD300c monoclonal antibody that induces M1 macrophage polarization, and anti-PD-1, an immune checkpoint inhibitor, in TNBC. To establish a TNBC model, 4T1 cells were inoculated into the fourth left mammary gland of mice. CL7 and anti-PD-1 were intravenously administered twice a week. Flow cytometry and RT-PCR were performed to assess the immunotherapeutic effects, and lung metastases were evaluated by the Hematoxylin and Eosin staining of lung tissues. Tumor growth was significantly reduced in the combination treatment group (CL7 and anti-PD-1) compared to both the PBS and monotherapy groups. Additionally, the combination treatment increased M1 macrophages and activated CD8+ T and NK cells in the tumor, while significantly suppressing lung metastases. These findings suggest that the combination of CL7 and anti-PD- therapy has the potential to treat TNBC by remodeling the TME. Full article

Background: The mechanical conditioning (MeCo) score is a multigene expression signature that is acquired by cancer cells in the primary breast tumor and is reflective of their responsiveness to ECM stiffness caused by tumor fibrosis. Chromatin remodeling downstream of mechanotransduction allows cancer cells to retain these acquired aggressive features even in the absence of mechanical stimulation from the primary tumor microenvironment, for instance, after dissemination through systemic circulation during metastasis. Importantly, patients who have high MeCo score tumors are at higher risk of developing metastatic breast cancer, compared to those with low MeCo scores. Moreover, circulating tumor cells (CTCs) are associated with a higher rate of metastatic dissemination, making CTC detection in the circulation of patients with breast cancer a significant prognostic biomarker for breast cancer metastasis. Beyond their enumeration per blood volume units, specific prognostic features of CTCs are not fully explored. We sought to determine whether MeCo scores increase stepwise along the metastatic cascade, from primary tumors to CTCs to distant metastatic colonization, using patient-matched biopsies. Methods: CTCs were isolated from the peripheral blood of two patient cohorts: patients with early-stage breast cancer using immunomagnetic enrichment/FACS methodology; and patients with late-stage breast cancer using the ANGLE Parsortix microfluidics system. Gene expression profiling using RNA-seq was performed on CTCs and matched primary tumors (PTs) in the early-stage cohort, and on CTCs and matched metastases (METs) for the late-stage cohorts. A quantile normalization approach was used to allow comparison across cohorts and MeCo scores were computed for all samples. The Wilcoxon matched-pairs signed rank test was performed for the comparison of MeCo scores from matching samples within each cohort; the Mann–Whitney unpaired test was used to compare MeCo scores of CTCs across cohorts. Results: In 12 pairs of patients with early-stage breast cancer, MeCo scores in CTCs were significantly higher than in their matched PTs (p = 0.026). Additionally, in 26 pairs of metastatic patient CTCs and METs, MeCo scores were significantly higher in METs compared to matched CTCs (p = 0.0004). MeCo scores of CTCs were similar between patients with early- and late-stage breast cancers, despite differing CTC isolation strategies (epitope-dependent and microfluidics size gradient). Notably, 98% of the genes in the MeCo score were present across evaluable CTC, MET, and PT samples. Conclusions: Our results show that the MeCo score is higher in CTCs than in PTs, and higher in METs compared to CTCs, in early- and late-stage breast cancer, respectively (i.e., PT < CTC < MET). Therefore, the MeCo score is progressively higher throughout the metastatic cascade in breast cancer. These findings demonstrate that mechanical conditioning from primary tumors is retained during metastatic progression, after mechanical induction by ECM stiffness is lost, as cancer cells disseminate through systemic circulation. Additionally, these findings support that cancer cells with higher MeCo scores are more competent with—and potentially selected for—metastatic progression. Importantly, these findings provide a novel feature of CTCs, mechanical conditioning (MeCo), which is associated with higher capacity for metastasis. Furthermore, since the CTC MeCo score is elevated even in early-stage breast cancer, it could provide, in addition to CTC enumeration, a potential prognostic indicator to improve metastatic risk assessment in early disease. Full article

Bone metastases are a prevalent and debilitating consequence of various cancers, including breast and prostate carcinomas, which significantly compromise patient quality of life due to pain, fractures, and other skeletal-related events (SREs). This review examines the pathophysiology of bone metastases, emphasizing the role of the bone microenvironment in tumor progression through mechanisms such as osteotropism and the dysregulated bone remodeling cycle. The primary focus is on the emerging nano-drug delivery systems (DDS) designed to target the bone microenvironment and improve the therapeutic index of anticancer agents. Current treatments, mainly comprising bisphosphonates and radiotherapy, provide palliative benefits but often have limited efficacy and significant side effects. Innovative strategies, such as bisphosphonate-conjugated nanoparticles and targeted therapies that utilize the unique bone marrow niche, are explored for their potential to enhance drug accumulation at metastatic sites while minimizing systemic toxicity. These approaches include the use of liposomes, polymeric nanoparticles, and inorganic nanoparticles, which can be functionalized to exploit the biological barriers within the bone microenvironment. This review also discusses the challenges and future directions for nano-DDS in clinical settings, emphasizing the need for multidisciplinary research to effectively integrate these technologies into standard care protocols. Full article

Doxorubicin (DOX) is used for the treatment of various malignancies, including leukemias, lymphomas, sarcomas, and bladder, breast, and gynecological cancers in adults, adolescents, and children. However, DOX causes severe side effects in patients, such as cardiotoxicity, which encompasses heart failure, arrhythmia, and myocardial infarction. DOX-induced cardiotoxicity (DIC) is based on the combination of nuclear-mediated cardiomyocyte death and mitochondrial-mediated death. Oxidative stress, altered autophagy, inflammation, and apoptosis/ferroptosis represent the main pathogenetic mechanisms responsible for DIC. In addition, in vitro and in vivo models of DIC sirtuins (SIRT), and especially, SIRT 1 are reduced, and this event contributes to cardiac damage. In fact, SIRT 1 inhibits reactive oxygen species and NF-kB activation, thus improving myocardial oxidative stress and cardiac remodeling. Therefore, the recovery of SIRT 1 during DIC may represent a therapeutic strategy to limit DIC progression. Natural products, i.e., polyphenols, as well as nano formulations of DOX and iron chelators, are other potential compounds experimented with in models of DIC. At present, few clinical trials are available to confirm the efficacy of these products in DIC. The aim of this review is the description of the pathophysiology of DIC as well as potential drug targets to alleviate DIC. Full article

The biomechanical properties of the extracellular matrix (ECM) including its stiffness, viscoelasticity, collagen architecture, and temperature constitute critical biomechanical cues governing breast cancer progression. Matrix metalloproteinase 13 (MMP13) is an important marker of breast cancer and plays important roles in matrix remodelling and cell metastasis. Emerging evidence highlights MMP13 as a dynamic modulator of the ECM’s physical characteristics through dual mechanoregulatory mechanisms. While MMP13-mediated collagen degradation facilitates microenvironmental softening, thus promoting tumour cell invasion, paradoxically, its crosstalk with cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) drives pathological stromal stiffening via aberrant matrix deposition and crosslinking. This biomechanical duality is amplified through feedforward loops with an epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) populations, mediated by signalling axes such as TGF-β/Runx2. Intriguingly, MMP13 exhibits context-dependent mechanomodulatory effects, demonstrating anti-fibrotic activity and inhibiting the metastasis of breast cancer. At the same time, angiogenesis and increased metabolism are important mechanisms through which MMP13 promotes a temperature increase in breast cancer. Targeting the spatiotemporal regulation of MMP13’s mechanobiological functions may offer novel therapeutic strategies for disrupting the tumour–stroma vicious cycle. Full article