Search Results (3,351)

Alterations in the mitochondrial genome (mtDNA) have been shown to be key in cancer development and could be useful as biomarkers for diagnosis, prognosis, and treatment. To identify mtDNA variants associated with breast cancer, we analyzed the whole mtDNA sequence from paired tissues (tumor–peripheral blood) of women with this malignancy and from peripheral blood samples of healthy women. The mtDNA mutational landscape, heteroplasmy levels of the variants, and mitochondrial ancestry were established. Comparative analysis between cases and controls revealed significant differences in the number and location of variants, as well as in the heteroplasmy levels. Cases showed higher mutation number in MT-ND5, tRNAs, and rRNAs genes; increased proportion of missense variants; and elevated mtDNA content, than controls. Notably, a high blood mtDNA mutational burden (OR = 3.83, CI: 1.89–7.95, p = 5.3 × 10⁻⁵) and five mtDNA variants showed association with the risk of breast cancer. Furthermore, a low tumor mutational burden (HR = 7.82, CI: 1.0–63.6, p = 0.05) and the haplogroup L (HR = 12.16, CI: 2.0–72.8, p = 0.0062) were associated with decreased overall and disease-free survival, respectively. Our study adds evidence of the potential usefulness of mtDNA variants as risk and prognosis biomarkers for breast cancer. Full article

Breast cancer (BC) remains a leading cause of cancer-related mortality in women. Extracellular matrix (ECM) remodeling is a critical modulator of tumor invasion and metastasis. Three-dimensional (3D) cell culture models have been proposed as advanced systems better mimicking the tumor microenvironment (TME), potentially offering enhanced insights into underlying mechanisms compared to conventional two-dimensional (2D) cultures. This study highlights how BC cells develop metastatic potential and tumor progression independently from ECM contact using advanced 3D spheroid culture models compared to traditional 2D cultures in triple-negative breast cancer (TNBC) cell lines. Spheroids were formed using ultra-low adhesion plates, and their morphological and functional properties were assessed via phase-contrast and scanning electron microscopy (SEM), along with functional assays. Both cell lines formed compact spheroids exhibiting mesenchymal-to-epithelial transition (MET) characteristics. Functional assays showed enhanced cell migration and dissemination of spheroid-derived cancer cells. Gene expression profiling revealed increased expression of ECM remodeling enzymes, cell surface receptors, and adhesion molecules in 3D cultures compared to 2D. MicroRNA analysis highlighted distinct regulatory patterns specifically associated with metastasis and epithelial-to-mesenchymal transition (EMT). These findings demonstrate that 3D spheroid models effectively recapitulate the complexity of TNBC, providing valuable insights into ECM dynamics, epigenetic regulation, and metastatic behavior and potentially guiding improved therapeutic strategies. Full article

Background: Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women. Hereditary BC risk accounts for 25% of all cases. Pathological variants in known BC precursor genes explain only about 30% of hereditary BC cases, while the underlying genetic factors in most families remain unknown. Identifying hereditary cancer risk factors will help improve genetic counseling, cancer prevention, and cancer care. Methods: Here, we used whole-exome sequencing (WES) to identify genetic variants in 105 Vietnamese patients with BC and 50 healthy women. BC-associated variants were screened by the Franklin software and the criteria of the American College of Medical Genetics and Genomics (ACMG) and evaluated based on in silico analysis. Results: In total, 56 variants were identified in 37 genes associated with BC, including ACVR1B, APC, AR, ARFGEF1, ATM, ATR, BARD1, BLM, BRCA1, BRCA2, CASP8, CASR, CHD8, CTNNB1, ESR1, FAN1, FGFR2, HMMR, KLLN, LZTR1, MCPH1, MLH1, MSH2, MSH3, MSH6, NF1, PMS2, PRKN, RAD54L, RB1CC1, RECQL, SLC22A18, SLX4, SPTBN1, TP53, WRN, and XRCC3 in 41 patients. Among them, 12 variants were novel, and 10 variants were assessed as pathogenic/likely pathogenic by ACMG and ClinVar. Variants of uncertain significance (VUS) were evaluated using in silico prediction software to predict whether they are likely to cause the disease in patients. Conclusions: This is the first WES study to identify BC-associated genetic variants in Vietnamese patients, providing a comprehensive database of BC susceptibility gene variants. We suggest using WES as a tool to identify genetic variants in BC patients for risk prediction and treatment guidance. Full article

MicroRNAs (miRNAs) are well known for regulating translation in the cytoplasm, yet their nuclear roles remain poorly understood. Previously, we identified spliceosome-associated miRNAs implicated in tumorigenesis and metastasis in breast cancer models. Here, we investigate their nuclear functions in the immortalized human cortical neuron (HCN) cell line, along with glioblastoma (U87MG) and neuroblastoma (SH-SY5Y) cell lines, both widely used as models for brain cancer research. Our findings reveal that spliceosome-associated miRNAs mark neuronal cancer cells and uncover novel nuclear targets. Notably, some spliceosomal miRNAs exhibit opposing regulatory effects in the nucleus compared to the cytoplasm, while others demonstrate potential novel nuclear functions. A prominent example is miR-99b, which overlaps the 5′ splice junction of the poorly characterized long non-coding RNA (lncRNA)sperm acrosome-associated 6 antisense RNA1 (SPACA6-AS1) and, through base pairing, enhances SPACA6-AS1 pre-mRNA levels. These results highlight the diverse and context-dependent functions of nuclear miRNAs in gene regulation and cancer progression, broadening our understanding of their regulatory potential beyond the cytoplasm. Full article

Background: Breast cancer, particularly the luminal subtype, often responds to endocrine therapies. However, 20–30% of patients develop resistance, resulting in more aggressive disease. Long non-coding RNAs (lncRNAs) are implicated in cancer progression and treatment resistance. Objective: This study aimed to evaluate the role of the lncRNA insulin-like growth factor 2 antisense (IGF2-AS) in tamoxifen-resistant breast cancer and assess its potential as a therapeutic target. Methods: Two tamoxifen-resistant breast cancer cell lines (TAMR-V and TAMR-H) were used to assess IGF2-AS expression via qPCR. Knockdown experiments with siRNA evaluated the role of IGF2-AS in cell proliferation, invasion, and migration. Next-generation sequencing (NGS) analyzed gene expression differences between the cell lines. Kaplan–Meier survival analysis determined the clinical significance of IGF2-AS expression in breast cancer patients. Results: IGF2-AS expression was significantly upregulated in TAMR-V and TAMR-H cell lines compared to control MCF-7 cells. Knockdown of IGF2-AS reduced cell proliferation and invasion in TAMR-V cells but did not significantly affect TAMR-H cells, indicating a cell line-specific role in tamoxifen resistance. NGS revealed differential gene expression profiles between TAMR-V and TAMR-H cells, suggesting variability in resistance mechanisms. Survival analysis demonstrated that higher IGF2-AS expression was associated with poorer prognosis in breast cancer patients, including those with hormone-positive and triple-negative subtypes. Conclusions: IGF2-AS is upregulated in tamoxifen-resistant breast cancer and promotes cell proliferation and invasion in a cell line-specific manner. Its differential expression in TAMR-V and TAMR-H cells highlights the complexity of resistance mechanisms, suggesting IGF2-AS as a potential therapeutic target for overcoming tamoxifen resistance. Full article

The breast microbiome remains stable throughout a woman’s life. The breast is not a sterile organ, and its microbiota exhibits a distinct composition compared to other body sites. The breast microbiome is a community characterized by an abundance of Proteobacteria and Firmicutes, which represent the result of host microbial adaptation to the fatty acid environment in the tissue. The breast microbiome demonstrates dynamic adaptability during lactation, responding to maternal physiological changes and infant interactions. This microbial plasticity modulates local immune responses, maintains epithelial integrity, and supports tissue homeostasis, thereby influencing both breast health and milk composition. Disruptions in this balance, the dysbiosis, are closely linked to inflammatory breast conditions such as mastitis. Risk factors for breast cancer (BC) include genetic mutations, late menopause, obesity, estrogen metabolism, and alterations in gut microbial diversity. Gut microbiota can increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties. Perturbations of this set of bacterial genes and metabolites, called the estrobolome, increases circulating estrogens and the risk of BC. Fusobacterium nucleatum has recently been associated with BC. It moves from the oral cavity to other body sites hematogenously. This review deals with the characteristics of the breast microbiome, with a focus on F. nucleatum, highlighting its dual role in promoting tumor growth and modulating immune responses. F. nucleatum acts both on the Wnt/β-catenin pathway by positively regulating MYC expression and on apoptosis by inhibiting caspase 8. Furthermore, F. nucleatum binds to TIGIT and CEACAM1, inhibiting T-cell cytotoxic activity and protecting tumor cells from immune cell attack. F. nucleatum also inhibits T-cell function through the recruitment of myeloid suppressor cells (MDSCs). These cells express PD-L1, which further reduces T-cell activation. A deeper understanding of F. nucleatum biology and its interactions with host cells and co-existing symbiotic microbiota could aid in the development of personalized anticancer therapy. Full article

In breast cancer, progression from localized stage I to distant metastatic stage IV disease is associated with a reduction of 5-year survival from nearly 100% to 23.2%. Expression of the calcium-activated protease isoforms calpain-1 and calpain-2 has been correlated with cell migration and invasion in vitro, metastatic potential in preclinical mouse models of cancer, and breast cancer prognosis in patients. It is unclear which of these two calpain isoforms is responsible for the apparent metastatic potential of cancer cells. Here, we demonstrate that while individual CRISPR-Cas9 knockouts of either CAPN1 or CAPN2 genes (encoding the catalytic subunits of calpain-1 and -2, respectively) reduce in vitro migration and marginally suppress in vivo metastasis, genetic disruption of both calpain-1 and calpain-2 through knockout of the CAPNS1 gene (encoding the common regulatory subunit of calpain-1 and -2) diminishes metastasis by 83.4 ± 13.6% in a mouse xenograft model of human triple-negative breast cancer. The effect of calpain-1/2 deficiency was replicated in vitro with a modified cell-permeable calpastatin (CAST)-based peptide inhibitor (cell migration reduced to 53.5 ± 11.0% of vehicle control). However, this peptide inhibitor was not effective in vivo at reducing metastasis under the conditions used (vehicle vs. CAST, 1.12 ± 1.35 lung metastases per mm² vs. 0.34 ± 0.20 metastases per mm²), likely due to rapid clearance, as indicated by the short serum half-life. This work demonstrates that calpain-1/2 disruption effectively abrogates metastasis and provides rationale for development of effective calpain inhibitors. Full article

Background and Aims: Triple-negative breast cancer (TNBC) is a clinically aggressive malignancy marked by rapid disease progression, limited therapeutic avenues, and high recurrence risk. Ferroptosis an iron-dependent, lipid peroxidation-driven form of regulated cell death that has emerged as a promising therapeutic vulnerability in oncology. This study delineates the ferroptosis-associated molecular architecture of TNBC to identify key regulatory genes with prognostic and translational significance. Methods: Transcriptomic profiles from the GSE103091 dataset (130 TNBC and 30 normal breast tissue samples) were analyzed to identify ferroptosis-related differentially expressed genes (DEGs) using GEO2R. Protein–protein interaction (PPI) networks were constructed via STRING and GeneMANIA, with functional enrichment performed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome analyses. Prognostic relevance was evaluated using GEPIA, BC-GenExMiner, and Kaplan–Meier Plotter survival analyses. Results: Six ferroptosis drivers (MAPK1, TLR4, IFNG, ATM, ULK2, and ATF3) and five suppressors (NFS1, GCLC, TP63, CD44, and SRC) were identified alongside HMOX1, a bifunctional regulator with context-dependent pro- and anti-ferroptotic activity. Enrichment analyses revealed significant associations with oxidative stress regulation, autophagy, immune modulation, and tumor progression pathways. Elevated IFNG expression was consistently linked to improve overall, disease-free, and distant metastasis-free survival, underscoring its dual function in antitumor immunity and ferroptosis sensitization. Conclusions: Ferroptosis represents a critical axis in TNBC pathophysiology, with IFNG emerging as both a prognostic biomarker and a viable therapeutic target. These insights provide a mechanistic foundation for integrating ferroptosis-inducing agents with immunotherapeutic modalities to enhance clinical outcomes and overcome therapeutic resistance in TNBC. Full article

Zinc is an essential trace element involved in critical physiological functions such as gene expression, immune regulation, and cellular proliferation. This review explores the link between zinc homeostasis and cancer, with a specific focus on LIV-1 zinc transporters and their potential relevance to cancer research and treatment priorities in Saudi Arabia, as informed by global data. Zinc homeostasis is maintained by two major transporter families: ZIP (SLC39A) and ZnT (SLC30A). The dysregulation of specific ZIP transporters, particularly ZIP4, ZIP7, ZIP6, and ZIP10, has been implicated in cancer progression. Bioinformatic analyses revealed the significant overexpression of ZIP4, ZIP7, and ZIP6 in breast cancer and ZIP4 in colorectal cancer, which are the most common cancers among Saudi women and men, respectively. Notably, ZIP4 and ZIP7 upregulation correlated with poorer clinical outcomes, whereas ZIP6 was positively associated with survival in breast cancer. These findings underscore the potential of zinc transporters as prognostic biomarkers and therapeutic targets. Despite the substantial global evidence, research on zinc transporters in the Saudi population remains limited. Considering the Kingdom’s rising cancer burden and unique genetic, environmental, and dietary factors, understanding zinc metabolism in this context is important. Targeted research may support precision medicine strategies and improve outcomes in line with Saudi Arabia’s healthcare transformation goals. Full article

Background/Objectives: Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and holds promise as a therapeutic strategy against cancers with elevated iron metabolism. However, many tumors evade ferroptosis through the upregulation of specialized antioxidant defense mechanisms. Here, we investigated ferroptosis susceptibility and resistance mechanisms in TSC models and in ovarian and breast cancer cell lines, aiming to identify potential therapeutic targets. Methods: Ferroptosis sensitivity was assessed using RSL3 and erastin. We explored the contribution of ferroptosis defense pathways using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA sequencing was performed to evaluate the expression of ferroptosis resistance genes and to explore NRF2-regulated transcriptional programs. Results: TSC2-deficient cells were resistant to RSL3- and erastin-induced ferroptosis. This resistance correlated with upregulation of ferroptosis defense genes, including NRF2 and its downstream targets. Pharmacological inhibition of NRF2 resensitized TSC2-deficient cells to ferroptosis, confirming a protective role for NRF2. However, FSP1 inhibition did not restore ferroptosis sensitivity in TSC2-deficient angiomyolipoma cells. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cells. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition to enhance ferroptosis sensitivity. FSP1 expression was not regulated by NRF2, suggesting that NRF2-targeted therapies alone may be insufficient to overcome ferroptosis resistance in certain cancer contexts. Conclusions: TSC2-deficient cells resist ferroptosis via an adaptive antioxidant response that protects against elevated iron-mediated lipid peroxidation. Our findings identify NRF2 and FSP1 as key, but mechanistically distinct, regulators of ferroptosis resistance. The differential efficacy of targeting these pathways across cancer types highlights the potential need for patient stratification. Dual targeting of NRF2 and FSP1 may offer an effective therapeutic strategy for iron-dependent, ferroptosis-resistant cancers. Full article

The pregnane X receptor (PXR), a ligand-activated nuclear receptor, plays a central role in regulating the metabolism of both endogenous substances and xenobiotics. In recent years, increasing evidence has highlighted its involvement in chronic diseases, particularly metabolic disorders and cancer. PXR modulates drug-metabolizing enzymes, transporters, inflammatory factors, lipid metabolism, and immune-related pathways, contributing to the maintenance of hepatic–intestinal barrier homeostasis, energy metabolism, and inflammatory responses. Specifically, in type 2 diabetes mellitus (T2DM), PXR influences disease progression by regulating glucose metabolism and insulin sensitivity. In obesity, it affects adipogenesis and inflammatory processes. In atherosclerosis (AS), PXR exerts protective effects through cholesterol metabolism and anti-inflammatory actions. In metabolic dysfunction-associated steatotic liver disease (MASLD), it is closely associated with lipid synthesis, oxidative stress, and gut microbiota balance. Moreover, PXR plays dual roles in various cancers, including hepatocellular carcinoma, colorectal cancer, and breast cancer. Currently, PXR-targeted strategies, such as small molecule agonists and antagonists, represent promising therapeutic avenues for treating metabolic diseases and cancer. This review comprehensively summarizes the structural features, signaling pathways, and gene regulatory functions of PXR, as well as its role in metabolic diseases and cancer, providing insights into its therapeutic potential and future drug development challenges. Full article

Leishmaniasis is caused by protozoan parasites from the genus Leishmania and remains one of the major threats to global health, impacting millions of people worldwide as well as animals including dogs. Several treatments have been used for managing leishmaniasis; nevertheless, drug resistance has emerged as an important obstacle to disease control. Therefore, there is an urgent need to discover new therapeutic targets. The aim of this work was to study the role played by the breast cancer associated 1 C-terminal (BRCT) domain from LmjPES protein (Pescadillo ribosomal biogenesis factor) in Leishmania major‘s pathogenesis through the construction of novel genomic tools. For this purpose, Leishmania integrative plasmids that were able to express the BRCT domain from LmjPES and a hypothetical defective LmjPES lacking this BRCT domain were constructed. It was observed that the overexpression of the aforementioned BRCT domain in L. major dysregulated the mRNA expression of 152 genes (95 up-regulated and 57 down-regulated) in respect to control parasites. Furthermore, clustering studies of these altered genes revealed an enrichment in genes related to metabolic processes, transporter activity, response to stimuli, and protein folding, which are categories described to be associated with the metacyclogenesis process and parasite survival. Interestingly, these genes reached normal levels of expression in parasites transfected with a defective LmjPES (a mutated gene lacking the coding sequence of the BRCT domain). In addition, it was found that the footpad of mice inoculated with LmjPES BRCT-overexpressing parasites had significantly greater inflammation compared to the size of the footpad of animals infected with the control parasites. Based on all these results, it was suggested that the BRCT domain from LmjPES might play a role in L. major‘s infection process and pathogenesis. Full article

Research into aggressive gynecologic cancers such as uterine serous carcinoma (USC) has recently evolved from chemotherapy to the development of drugs targeting specific biomarkers differentially expressed/active in tumor cells. One such target is HER2/neu, which plays an important role in the coordination of cell growth and differentiation. Importantly, when overexpressed and/or amplified in tumor cells, the downstream tyrosine kinase of HER2/neu becomes constitutively activated, causing dysregulated gene transcription. In breast cancer patients, HER2/neu has been successfully utilized for many years as a target for multiple monoclonal antibodies and more recently antibody–drug conjugates (ADCs). Use in gynecologic malignancies has been slower, however, due to recently identified unique characteristics of HER2/neu protein expression and gene amplification in biologically aggressive tumors such as USC including its major heterogeneity and lack of apical staining when compared to breast cancer. Accordingly, the use of optimal testing algorithms for HER2/neu status in patients with USC may have important implications for the development of novel, effective, and targeted treatment modalities against this lethal variant of endometrial cancer. In this review, we discuss HER2/neu gene expression in USC, evaluate the efficacy of HER2/neu-directed therapies in both preclinical and clinical settings, and discuss possible mechanisms of resistance to HER2/neu targeting agents. Full article

Background/Objectives: We analyzed clinical and radiological characteristics and prognostic factors specific to young patients with breast cancer (YBC) aged <30 years. Methods: This retrospective study included 132 women aged <30 years who underwent breast surgery between 2008 and 2013. The clinical and radiological findings of the patients were examined and compared according to recurrence or death status at follow-up. Disease-free survival (DFS) and overall survival (OS) rates were also assessed. Results: Most patients (mean age, 27.1 years) presented with palpable lesions (85.6%). Hormone receptor-positive/human epidermal growth factor receptor-negative cancer was the most common molecular subtype (59.8%), followed by triple-negative breast cancer (28.0%), with high Ki-67 expression (62.1%). Mammography and ultrasound detected abnormalities in 90.1% and 97.3% of patients, respectively, whereas magnetic resonance imaging detected abnormalities in all patients. During the follow-up period (8–10 years), 28.5% of the patients experienced recurrence and 11.5% died. The calculated DFS and OS at 5 years were 80.8% and 69.8% and 91.3% and 87.8% at 10 years, respectively. Statistically significant factors associated with DFS/OS included the BRCA1 gene mutation, with preoperative neoadjuvant chemotherapy, no hormone therapy, larger tumor size, negative hormone receptor status, high Ki-67 expression, and some radiological findings, including asymmetry with calcifications on mammography, no sonographic echogenic rind of mass, and mild vascularity on Doppler study. Conclusions: Our study highlights the aggressive nature of breast cancer in YBC aged <30 years, with relatively high rates of recurrence and mortality. Significant factors affecting prognosis may guide personalized treatment approaches and predict the prognosis. Full article

Background: Targeting tumor-associated macrophages (TAMs) is a promising immunotherapy for cancers, but current strategies are limited due to strategic caveats. PU.1 is a transcription factor required for macrophage generation and differentiation. To date, the effect of PU.1 inhibition on solid tumors is unknown. Methods: This study examines the anti-tumor effect of PU.1 inhibition and its mechanism using the small-molecule DB2313 in mouse melanoma and breast tumor models. Results: We found that inhibition of PU.1 by DB2313 suppresses B16-OVA melanoma and 4T1 breast tumor growth in mice. In the melanoma tumor model, DB2313 enhanced tumor recruitment of CD4⁺ T helper 1 (Th1) and cytotoxic T/natural killer (NK) cells by targeting TAMs. Transcriptome and targeted gene expression analyses revealed that PU.1 inhibition by DB2313 and small-interference RNAs enhances CXCL9 expression in bulk tumors, TAMs, and bone marrow-derived macrophages. The anti-tumor effects of DB2313 were abolished by depleting macrophages with clodronate or inhibiting the CXCL9-CXCR3 chemokine axis using CXCL9- or CXCR3-neutralizing antibodies. Conclusions: These results suggest that pharmacological inhibition of PU.1 suppresses tumor growth by at least promoting the infiltration of lymphocytes into tumors through the CXCL9-CXCR3 chemokine axis. Our study establishes a framework for developing TAM-modulating immunotherapies by targeting the transcriptional factor PU.1. Full article