Search Results (448)

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

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

The cell division cycle machinery has been regarded as a promising therapeutic target for several decades. One of the most prominent milestones in the approach to targeting the cancer cell cycle was the development and approval of CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib. These small-molecule therapeutics have exhibited remarkable anti-cancer efficacy and have become primary choices for treating steroid receptor-positive breast cancer at multiple stages. This epoch-making success of cell-cycle-targeting drugs was followed by the development of small molecules to target other cell cycle-regulatory proteins, such as CDK2, CDK1, WEE1 kinase, Aurora kinases, and polo-like kinases, while therapeutic strategies to overcome resistance to CDK4/6 inhibitors have been pursued. In this article, we focus on heterogeneous vulnerabilities of cancers as consequences of various genetic and epigenetic alterations in the cell cycle-regulatory network, and we discuss how next-generation cell-cycle-targeting drugs currently in the developmental pipeline could exploit these heterogeneous vulnerabilities in the cancer cell cycle. We hope to provide a forward-looking perspective on directions for therapeutic cell-cycle targeting in the advent of personalized precision medicine. Full article

Metastasis is still the leading cause of cancer-related death. It happens when disseminated tumor cells (DTCs) successfully navigate a series of steps and adapt to the unique conditions of distant organs. In this review, key molecular and immune mechanisms that shape metastatic spread, long-term survival, and eventual outgrowth are examined, with a focus on how tumor-intrinsic programs interact with extracellular matrix (ECM) remodeling, angiogenesis, and immune regulation. Gene networks that sustain tumor-cell plasticity and invasion are described, including EMT-linked transcription factors such as SNAIL and TWIST, as well as broader transcriptional regulators like SP1. Also, how epigenetic mechanisms, such as EZH2 activity, DNA methylation, chromatin remodeling, and noncoding RNAs, lock in pro-metastatic states and support adaptation under therapeutic pressure. Finally, proteases and matrix-modifying enzymes that physically and biochemically reshape tissues, including MMPs, uPA, cathepsins, LOX/LOXL2, and heparinase, are discussed for their roles in releasing stored growth signals and building permissive niches that enable seeding and colonization. In parallel, immune-evasion strategies that protect circulating and newly seeded tumor cells are discussed, including platelet-mediated shielding, suppressive myeloid populations, checkpoint signaling, and stromal barriers that exclude effector lymphocytes. A major focus is metastatic dormancy, cellular, angiogenic, and immune-mediated, framed as a reversible survival state regulated by stress signaling, adhesion cues, metabolic rewiring, and niche constraints, and as a key determinant of late relapse. Tumor-specific metastatic programs across mesenchymal malignancies (osteosarcoma, chondrosarcoma, and liposarcoma) and selected high-burden cancers (melanoma, hepatocellular carcinoma, glioblastoma, and breast cancer) are highlighted, emphasizing shared principles and divergent organotropisms. Emerging therapeutic strategies that target both the “seed” and the “soil” are also discussed, including immunotherapy combinations, stromal/ECM normalization, chemokine-axis inhibition, epigenetic reprogramming, and liquid-biopsy-enabled minimal residual disease monitoring, to prevent reactivation and improve durable control of metastatic disease. Full article

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

The widespread use of glyphosate-based herbicides (GBHs) has raised concerns about their potential role in hormone-sensitive cancers such as breast cancer. This systematic review aimed to evaluate preclinical evidence on the effects of glyphosate (pure compound) or glyphosate-based herbicide formulations (GBHs) exposure on breast cancer cell proliferation and related molecular pathways. A structured search was conducted across PubMed, ScienceDirect, and Springer Nature Link, Web of Science databases, covering studies published up to 9 November 2025, following a PROSPERO-registered protocol (ID: CRD42021238350). Eligible studies included original in vitro and in vivo preclinical research using human breast cancer cell lines (e.g., MCF-7, T47D, MDA-MB-231, MCF-12A, and MCF-10A) or relevant animal models. Outcomes assessed included cell viability, proliferation, tumor growth, apoptosis, cell cycle regulation, and molecular markers associated with endocrine signaling. Two reviewers independently screened and extracted data, resolving disagreements via discussion or third-party adjudication. From an initial pool of 699 articles, seven in vitro studies met the inclusion and quality criteria. Glyphosate exposure demonstrated weak estrogenic activity in ER-positive breast cancer cells, primarily via ERα modulation and altered gene expression related to proliferation and DNA repair. GBHs showed greater cytotoxic and epigenetic effects in non-tumorigenic cells, often independent of ER signaling. No included study employed in vivo breast cancer models. Overall, preclinical evidence suggests glyphosate may act as a weak endocrine disruptor under specific conditions, but findings are limited by the short-term in vitro designs, heterogeneous methodologies, and lack of chronic or in vivo data. Further research using long-term exposure and animal models is needed to clarify potential risks and inform regulatory and public health decisions. Full article

Breast cancer is the most frequent gynecological malignancy and the main cause of cancer death in the female population worldwide. One of the most significant challenges in its clinical management is the molecular heterogeneity of malignant breast tumors, which is reflected in the current molecular classification of these entities. In each of these tumor molecular subtypes, distinct genetic alterations are involved, and several intracellular signaling pathways contribute to defining their biological identity and clinical response. This literature review summarized the main classic and emerging biomarkers in breast cancer, along with the therapies associated with them. There are several classic biomarkers associated with this disease, such as estrogen and progesterone receptors, the HER2 receptor, and the Ki-67 cell proliferation marker. Given the limitations of these biomarkers, new biomarkers have been identified, including the TP53 tumor suppressor gene, the EGFR, different types of RNAs, plus epigenetic and immunological biomarkers. The integration of classic and emerging biomarkers along with new therapeutic targets in the clinical practice has promoted a thorough understanding of the high molecular complexity of breast cancer and the development of precision medicine strategies which increase the chances of therapeutic success. Full article

Triple Negative Breast Cancers (TNBCs) are heterogeneous and aggressive tumors with a median overall survival of less than two years. Despite the availability of new drugs, the prognosis remains poor, implicating a more aggressive clinical course in the metastatic setting. This study investigated the effects of metronomic treatment (mCHT) with 5-fluorouracil (5-FU) plus vinorelbine (VNR) on spheroids derived from two different TNBC cell lines (BT-549 and MDA-MB-231) and a patient-derived primary cell line (MS-186). mCHT significantly reduced spheroid growth and altered spheroid architecture, with a pronounced effect in second-generation spheroids, enriched in self-renewing cancer stem cells (CSCs). Expression of CSC-related markers (CD44, CD133, NOTCH-1, and MYC) was more significantly altered—both at the mRNA and protein levels—by mCHT than by standard treatment (STD). In MS-186-derived spheroids, mCHT downregulated EZH2 and STAT3, key regulators of CSC maintenance, and reduced H3K27ac, suggesting a global epigenetic reprogramming. Unlike STD, which partially and transiently reduced stemness markers, mCHT achieved sustained suppression, indicating preferential targeting of therapy-resistant CSCs. These results indicate mCHT as a promising strategy for specifically aiming at the CSC-like compartment in TNBC, underscoring a therapeutic approach that reprograms key epigenetic networks and overcomes resistance to treatment. Full article

Bone metastases remain a leading cause of morbidity and mortality in patients with advanced breast, prostate, and lung cancers. A striking clinical feature of bone metastasis is the ability of disseminated tumor cells (DTCs) to persist in a dormant state for years or even decades before reawakening to drive overt disease. While the molecular and microenvironmental cues that induce and maintain dormancy have been increasingly studied, the mechanisms governing dormancy escape remain poorly defined yet are critical for preventing relapse. In this review, we synthesize emerging evidence on how the bone microenvironment orchestrates the transition of dormant tumor cells into proliferative lesions. We discuss how osteoclast-mediated bone resorption liberates growth factors such as TGF-β and IGF-1, fueling reactivation; how loss of osteoblast-mediated quiescence signals disrupts the endosteal niche; and how bone marrow adipocytes provide metabolic support through lipid transfer and adipokine secretion. We highlight the role of immune surveillance in maintaining dormancy and how immunosuppressive myeloid populations, regulatory T cells, and inflammatory triggers, such as neutrophil extracellular traps, promote escape. Additional emphasis is placed on extracellular matrix remodeling, mechanotransduction, angiogenic switching, and systemic factors, including aging, hormonal changes, and sympathetic nervous system activation. We also review epigenetic and metabolic reprogramming events within dormant cells that enable reactivation. Finally, we evaluate therapeutic strategies to sustain dormancy or prevent reawakening, including osteoclast-targeted therapies, immune-modulating approaches, and epigenetic or metabolic interventions. By integrating these insights, we identify key knowledge gaps and propose future directions to intercept dormancy escape and delay or prevent metastatic relapse in bone. Full article

High mobility group A1 (HMGA1) is a chromatin-associated protein that regulates transcription and drives cancer progression. In this pan-cancer study, we analyzed multi-omics data to comprehensively characterize HMGA1’s expression patterns, prognostic significance, epigenetic regulation, and immunotherapy roles. We found that HMGA1 was markedly upregulated in most cancers, mainly driven by promoter hypomethylation and copy number alterations. Elevated HMGA1 expression was consistently associated with unfavorable patient survival, stemness features, and the activation of oncogenic signaling pathways. Crucially, HMGA1 expression correlated with an immune-excluded tumor microenvironment, characterized by suppressed stromal and immune scores. Even in tumors with immune infiltration, high HMGA1 predicted poor prognosis, likely mediated by enhanced regulatory T-cell (Treg) recruitment and impaired effector immune function. Moreover, HMGA1 levels were positively correlated with tumor mutational burden (TMB), and microsatellite instability (MSI), and immunotherapy-related checkpoints including PD-1, CTLA-4, and TIGIT. Drug sensitivity analysis further revealed that HMGA1 predicted resistance to AKT inhibitors, which was experimentally validated in breast cancer cells treated with Capivasertib. Collectively, our findings establish HMGA1 as a pivotal oncogenic regulator and a promising biomarker for prognosis and for guiding strategies in immunotherapy and overcoming targeted therapy resistance. Full article

Ganoderma lucidum has long been recognized for its medicinal properties, particularly due to its antioxidant, anti-inflammatory, and pro-apoptotic components such as polysaccharides and triterpenoids. This study aimed to evaluate the cytotoxic and molecular effects of ethanol and methanol extracts of G. lucidum as well as doxorubicin on MCF-7 breast cancer cells. The cytotoxicity was assessed via MTT assay. The methanol extract showed stronger cytotoxicity (IC₅₀: 62.37 µg/mL) than the ethanol extract, while doxorubicin exhibited an IC₅₀ value of 0.66 mM. Phenolic profiling by HPLC revealed high levels of vanillic acid, gallic acid and (−)-epicatechin in the methanol extract, while volatile compounds such as hexanal and acetic acid were identified by GC-MS. Flow cytometric analysis demonstrated G0/G1 phase cell cycle arrest and an increase in early and late apoptotic populations. Gene expression studies using RT-qPCR showed significant downregulation of ACAT1, ADCY3, and NME2, key regulators of energy metabolism and epigenetic modification. On the other hand, doxorubicin treatment upregulated ACAT1 and ADCY3, while a slight downregulation was observed in NME2. These molecular changes suggest that G. lucidum induces apoptosis and impairs cancer cell proliferation through metabolic disruption and gene modulation. Full article

For decades, cancer risk has been explained mainly by local factors. However, emerging evidence shows that the oral microbiome acts as a systemic modifier of oncogenesis well beyond the head and neck. This review synthesizes clinical and mechanistic data linking dysbiotic oral communities, especially Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola, to malignancies across gastrointestinal, respiratory, hepatobiliary, pancreatic, breast, and urogenital systems. We summarize organ-specific associations from saliva, tissue, and stool studies, noting the recurrent enrichment of oral taxa in tumor and peri-tumoral niches of oral, esophageal, gastric, colorectal, lung, pancreatic, liver, bladder, cervical, and breast cancers. Convergent mechanisms include the following: (i) persistent inflammation (lypopolysacharide, gingipains, cytolysins, and collagenases); (ii) direct genotoxicity (acetaldehyde, nitrosation, and CDT); (iii) immune evasion/suppression (TLR/NLR signaling, MDSC recruitment, TAN/TAM polarization, and TIGIT/CEACAM1 checkpoints); and (iv) epigenetic/signaling rewiring (NF-κB, MAPK/ERK, PI3K/AKT, JAK/STAT, WNT/β-catenin, Notch, COX-2, and CpG hypermethylation). Plausible dissemination along an oral–gut–systemic axis, hematogenous, lymphatic, microaspiration, and direct mucosal transfer enables distal effects. While causality is not yet definitive, cumulative data support oral dysbiosis as a clinically relevant cofactor, motivating biomarker-based risk stratification, saliva/stool assays for early detection, and microbiome-targeted interventions (periodontal care, antimicrobials, probiotics, and microbiota modulation) alongside conventional cancer control. Full article

Breast cancer (BC) is increasingly recognized as a heterogeneous disease, with complexity that extends beyond the classical luminal A/B, HER2-enriched, and triple-negative framework. Advances in molecular and functional profiling have uncovered emerging subpopulations, including HER2-low, claudin-low, BRCA-deficient (“BRCAness”), and refined TNBC subsets, such as luminal AR (LAR) and basal-like immune variants, that extend beyond traditional taxonomies. These novel classifications provide additional resolutions, offering both prognostic insight and therapeutic opportunities. In this comprehensive review, we integrate evidence from genomic, epigenetic, proteomic, immune-related, and liquid biopsy biomarkers, underscoring how they define the biology of these subgroups and predict responses to targeted therapies, such as antibody–drug conjugates, PARP inhibitors, and immune checkpoint blockade. We further highlight the role of the tumor microenvironment (TME) and intratumoral heterogeneity in shaping these entities. Collectively, recognition of emerging subtypes as clinically actionable groups represents a paradigm shift from static receptor-based models to dynamic, biomarker-driven frameworks that refine prognosis, enable patient stratification, and support precision oncology in aggressive BC. Full article

Breast cancer remains the leading cause of cancer-related death in women worldwide. This disease is characterized by its molecular and phenotypic heterogeneity, which hinders the development of effective therapies. While two-dimensional (2D) monolayer cell cultures are widely used, they are insufficient to reproduce the characteristics of the tumor microenvironment, thus limiting our understanding of cancer biology. In this context, three-dimensional (3D) models have emerged as representative tools that more accurately reproduce tissue architecture, cell signaling, and nutrients and oxygen gradients. These cellular models offer greater similarity to primary tissues, improving the study of relevant biological processes. Although 3D cultures provide numerous advantages in cancer research, there is no unified model that standardizes the matrix type and parameters such as gelation time or porosity, hindering the reproducibility and interpretability of the data. This review integrates evidence from various studies to evaluate the effect of epigenetic variations generated by 3D culture methods, which are regulated by mechanotransduction and, consequently, by signaling pathways such as integrin/FAK-ILK/Rho-YAP derived from interactions of cells with extracellular matrix-enriched scaffolds. This affects processes such as DNA methylation, histone coding, and the regulation of non-coding RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in different molecular subtypes of breast cancer. Overall, the evidence highlights that 3D culture methods are not equivalent but rather generate distinct epigenetic signatures at the non-coding RNA level that influence the proliferation, differentiation, therapeutic resistance, and metastatic potential of tumor cells. Furthermore, the evidence suggests that histone coding patterns, primarily through the reduction of acetylation marks, are conserved regardless of the type of 3D culture. In summary, the study highlights that the microarchitectural and compositional characteristics of 3D scaffolds are key determinants of epigenetic plasticity. Full article

Studies have widely indicated that the composition of maternal nutrition and diets might affect offspring health later in life. Studies on paternal contribution to the offspring’s disease are relatively scarce but are an important subject to the field. Recent research has suggested that paternal factors influenced by nutrition have been implicated in the transgenerational heritage of health and diseases through epigenetic mechanisms. This review aims to explore the current state of knowledge on nutrition-based paternal impacts on gynecological disease through epigenetics, focusing on the transmission of cancer and metabolic diseases from father to female offspring. We will explore the various mechanisms by which epigenetic landmarks, such as DNA methylation, histone modifications, and non-coding RNAs, are passed on through sperm and reprogrammed in the embryo, influencing offspring development and health. We will discuss the impacts of preconception paternal nutrition on two common cancer such as breast cancer and ovarian cancer in female offspring. Additionally, paternal overweight or obesity has been associated with increased risk of obesity in the offspring and compromised metabolic health, which may link to reproductive conditions such as infertility. Understanding the molecular mechanisms underlying non-genetic inheritance is crucial for elucidating the nutrition-mediated developmental origins of health and disease. This review highlights the mechanistic correlation between preconception paternal nutrition and female offspring gynecological health. Furthermore, it emphasizes the need for additional research to establish evidence-based paternal nutrition consultation and guidelines aimed at optimizing reproductive health and pregnancy outcomes in couples planning to conceive. Full article