Search

This research endeavors to investigate the functions of N6-methyladenosine (m6A) regulatory genes and key genes linked to m6A modifications within the context of breast cancer (BC). The objective is to identify a promising predictive biomarker related to m6A modifications and validate its significance in BC through experimental methodologies. Utilizing data from The Cancer Genome Atlas (TCGA) database, a model for predicting prognosis was developed. Key genes connected to m6A modifications were discerned using weighted gene co-expression network analysis (WGCNA) coupled with LASSO and Cox regression analyses, which were then utilized to construct a predictive model. The influence of ZNF260 within BC was probed experimentally. The predictive model formulated using m6A regulatory genes and key m6A-associated genes demonstrated the capability to categorize BC patients into distinct risk groups effectively (all P < 0.001). Clinical sample analyses revealed notably elevated expression levels of ZNF260 in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2−) BC tissues compared to adjacent non-tumor tissues (all P < 0.001). Reduction in ZNF260 expression was shown to inhibit the proliferation, clonogenicity, migration, and invasiveness of MCF-7 cells while concomitantly enhancing apoptosis (all P < 0.001).This investigation uniquely uncovered ZNF260 as a novel key gene, suggesting its potential utility as a predictive biomarker associated with m6A modifications specifically in HR + /HER2− BC. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with an unmet clinical need, but its epigenetic regulation remains largely undefined. By performing multiomic profiling, we recently revealed distinct super-enhancer (SE) patterns in different subtypes of breast cancer and identified a number of TNBC-specific SEs that drive oncogene expression. One of these SEs, TCOF1 SE, was discovered to play an important oncogenic role in TNBC. However, the molecular mechanisms by which TCOF1 SE promotes the expression of the TCOF1 gene remain to be elucidated. Here, by using combinatorial approaches of DNA pull-down assay, bioinformatics analysis and functional studies, we identified FOSL1 as a key transcription factor that binds to TCOF1 SE and drives its overexpression. shRNA-mediated depletion of FOSL1 results in significant downregulation of TCOF1 mRNA and protein levels. Using a dual-luciferase reporter assay and ChIP-qPCR, we showed that binding of FOSL1 to TCOF1 SE promotes the transcription of TCOF1 in TNBC cells. Importantly, our data demonstrated that overexpression of FOSL1 drives the activation of TCOF1 SE. Lastly, depletion of FOSL1 inhibits tumor spheroid growth and stemness properties of TNBC cells. Taken together, these findings uncover the key epigenetic role of FOSL1 and highlight the potential of targeting the FOSL1-TCOF1 axis for TNBC treatment. [ABSTRACT FROM AUTHOR]

Gene delivery has emerged as a novel and effective method in the treatment of malignancies within medical interventions by applying nanotechnology. Consequently, the development of appropriate nanocarriers is a key focus of this research. Dynamic light scattering (DLS), fourier transform infrared (FT-IR) spectroscopy, x-ray diffraction (XRD), and thermal gravimetric analysis (TGA) were employed for the characterization of the synthesized nanocarrier. Furthermore, to assess the gene transfer capability of the nanocarrier, various techniques such as gel retardation assay, nuclease resistance assay, cytotoxicity assay, flow cytometry, and transfection were employed. The average particle size and zeta potential of the GO-CS@Ca nanocarrier were obtained as 319.8 nm and + 92.8 mv, respectively. In the gel retardation test, it was observed that pDNA was effectively condensed by the GO-CS@Ca nanocarrier. The results of the MTT assay indicated that both GO-CS@Ca nanocarrier and the GO-CS@Ca/pDNA nanoplex with low toxicity. In flow cytometry analysis, it was observed that the complexation of pDNA with the GO-CS@Ca nanocarrier resulted in effective gene delivery to the MCF-7 cell line and consequently increased apoptosis induction. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer (BRCA) is the most common malignant tumor among women, characterized by high incidence rates and mortality rates. Oxidative stress and immunity, particularly in relation to mitochondria, have emerged as pivotal factors in breast carcinogenesis. Nonetheless, limited research has explored the specific contribution of mitochondrial oxidative stress to the prognosis of BRCA. Method: In this study, we conducted univariate and multivariate Cox regression analyses to pinpoint independent prognostic genes associated with mitochondrial oxidative stress (MOSRGs) and their correlation with BRCA clinical outcomes. Subsequently, we developed a robust and accurate MOS scoring system for BRCA patients based on these identified independent prognostic MOSRGs. Result: Our findings were further substantiated by immune infiltration and somatic mutation analyses, providing additional evidence that the MOS scoring system holds predictive value for clinical outcomes in patients and correlates directly with three subtypes of BRCA. In vitro experiments in the MCF7 cell and breast tissue further verified the mRNA and protein expression level of independent prognostic genes, validating the consistency of the MOS prognostic signatures in BRCA. Conclusion: This research has unveiled a novel prognostic scoring system, providing valuable insights for improving patient prognosis assessment and developing individualized treatment strategies in BRCA patients. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BRCA) represents a substantial global health challenge marked by inadequate early detection rates. The complex interplay between the tumor immune microenvironment and fatty acid metabolism in BRCA requires further investigation to elucidate the specific role of lipid metabolism in this disease. Methods: We systematically integrated nine machine learning algorithms into 184 unique combinations to develop a consensus model for lipid metabolism-related prognostic genes (LMPGS). Additionally, transcriptomics analysis provided a comprehensive understanding of this prognostic signature. Using the ESTIMATE method, we evaluated immune infiltration among different risk subgroups and assessed their responsiveness to immunotherapy. Tailored treatments were screened for specific risk subgroups. Finally, we verified the expression of key genes through in vitro experiments. Results: We identified 259 differentially expressed genes (DEGs) related to lipid metabolism through analysis of the cancer genome atlas program (TCGA) database. Subsequently, via univariate Cox regression analysis and C-index analysis, we developed an optimal machine learning algorithm to construct a 21-gene LMPGS model. We used optimal cutoff values to divide the lipid metabolism prognostic gene scores into two groups according to high and low scores. Our study revealed distinct biological functions and mutation landscapes between high-scoring and low-scoring patients. The low-scoring group presented a greater immune score, whereas the high-scoring group presented enhanced responses to both immunotherapy and chemotherapy drugs. Single-cell analysis highlighted significant upregulation of CPNE3 in epithelial cells. Moreover, by employing molecular docking, we identified niclosamide as a potential targeted therapeutic drug. Finally, our experiments demonstrated high expression of MTMR9 and CPNE3 in BRCA and their significant correlation with prognosis. Conclusion: By employing bioinformatics and diverse machine learning algorithms, we successfully identified genes associated with lipid metabolism in BRCA and uncovered potential therapeutic agents, thereby offering novel insights into the mechanisms and treatment strategies for BRCA. [ABSTRACT FROM AUTHOR]

Background: Anlotinib, a highly selective inhibitor of VEGFR2, has demonstrated significant anti-tumor effects in various cancers. However, its potential synergistic effects with DDP (cisplatin) in breast cancer (BRCA) remain to be fully elucidated. This study aims to discover the therapeutic efficacy of anlotinib on BRCA, specifically the synergistic effects with DDP, and to elucidate the underlying molecular mechanisms. Methods: BRCA cells were treated with anlotinib and/or DDP. The proliferation, migration and invasion capabilities of BRCA cells were evaluated using CCK-8 assays, cell cycle distribution, clone formation assays, wound healing assays and transwell assays. Cell apoptosis was detected by flow cytometry technique and Hoechst33342 fluorescence staining. The potential mechanism of anlotinib in the development of BRCA was predicted through bioinformatics analysis, and the mRNA or protein levels were subsequently quantified using qPCR, immunofuorescence and western blot. The anti-breast cancer efficacy of anlotinib was evaluated in vivo using a xenograft tumor model. Results: Our findings reveal that increased VEGFA expression in BRCA patients is associated with poorer prognosis, underscoring the need for targeted therapeutic strategies. We also demonstrate that both anlotinib and DDP independently inhibit BRCA cell growth, migration, and invasion, while their combination exhibits a synergistic effect, significantly enhancing the inhibition of these oncogenic processes. This synergy is further evident through the induction of apoptosis and autophagy in BRCA cells. Mechanistically, anlotinib's effectiveness is linked to its inhibition of the JAK2/STAT3 pathway, a critical axis in BRCA progression. In vivo study further support these results, showing that anlotinib markedly inhibits tumor growth in xenografted mice. Conclusion: This study confirms the efficacy of anlotinib or in combination with DDP and elucidates the mechanism behind anlotinib's effectiveness, highlighting its role in inhibiting the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Background: Natural killer (NK) cells play crucial roles in mediating anti-cancer activity in breast cancer (BRCA). However, the potential of NK cell-related molecules in predicting BRCA outcomes and guiding personalized therapy remains largely unexplored. This study focused on developing a prognostic and therapeutic prediction model for BRCA by incorporating NK cell-related genes. Methods: The data analyzed primarily originated from the TCGA and GEO databases. The prognostic role of NK cells was evaluated, and marker genes of NK cells were identified via single-cell analysis. Module genes closely associated with immunotherapy resistance were identified by bulk transcriptome-based weighted correlation network analysis (WGCNA). Following taking intersection and LASSO regression, NK-related genes (NKRGs) relevant to BRCA prognosis were screened, and the NK-related prognostic signature was subsequently constructed. Analyses were further expanded to clinicopathological relevance, GSEA, tumor microenvironment (TME) analysis, immune function, immunotherapy responsiveness, and chemotherapeutics. Key NKRGs were screened by machine learning and validated by spatial transcriptomics (ST) and immunohistochemistry (IHC). Results: Tumor-infiltrating NK cells are a favorable prognostic factor in BRCA. By combining scRNA-seq and bulk transcriptomic analyses, we identified 7 NK-related prognostic NKRGs (CCL5, EFHD2, KLRB1, C1S, SOCS3, IRF1, and CCND2) and developed an NK-related risk scoring (NKRS) system. The prognostic reliability of NKRS was verified through survival and clinical relevance analyses across multiple cohorts. NKRS also demonstrated robust predictive power in various aspects, including TME landscape, immune functions, immunotherapy responses, and chemotherapeutic sensitivity. Additionally, KLRB1 and CCND2 emerged as key prognostic NKRGs identified through machine learning and external validation, with their expression correlation with NK cells confirmed in BRCA specimens by ST and IHC. Conclusions: We developed a novel NK-related gene signature that has proven valuable for evaluating prognosis and treatment response in BRCA, expecting to advance precision medicine of BRCA. [ABSTRACT FROM AUTHOR]

Simple Summary: Lynch syndrome (LS) is an autosomal dominant disorder linked to increased risks of colorectal and endometrial cancers, caused by pathogenic variants in MMR genes (MLH1, MSH2, MSH6). In a cohort of 42,828 participants from the Taiwan Precision Medicine Initiative (TPMI), 89 individuals carried MMR gene variants: 25% MLH1, 53% MSH2, and 22% MSH6, with a prevalence of 1 in 481. Cancer incidence rates were 40.9% for MLH1, 29.8% for MSH2, and 40% for MSH6 carriers. Colonoscopy screening revealed no significant differences in polyp prevalence compared to controls. The study underscores the need for improved LS diagnosis and surveillance in the Taiwanese population. Lynch syndrome (LS) is an autosomal dominant disorder characterized by increased risks of colorectal and endometrial cancers. LS is defined by pathogenic variants in mismatch repair (MMR) genes, including MLH1, MSH2, and MSH6. Data on the prevalence and associated cancer risks of LS in the Han Chinese population remain limited. In this study, using a broad biobank approach through the Taiwan Precision Medicine Initiative (TPMI), we identified LS-associated MMR gene variants within a cohort of 42,828 participants from a Taiwanese medical center. A total of 89 individuals were found to carry pathogenic MMR variants: MLH1 (n = 22, 25%), MSH2 (n = 47, 53%), and MSH6 (n = 20, 22%). The overall prevalence of MMR variants was calculated, and cancer incidence rates among carriers were determined. The prevalence of MMR variants in the study population was 1 in 481. The distribution of MLH1, MSH2, and MSH6 variants were 24.7%, 52.8%, and 22.5%, respectively. Cumulative cancer incidence rates of carriers were 40.9% for MLH1 carriers, 29.8% for MSH2, and 40% for MSH6. Among the 19 individuals who underwent colonoscopy screening, the prevalence of polyps was similar to that of the control group (adenoma detection rate: 32% vs 26%, p = 0.585). A meticulous analysis of the detected polyps in seven participants, considering factors such as location, size, morphology, and pathological features, showed no significant differences from controls. A significant cancer risk is associated with LS-related MMR variants in the Taiwanese population. The apparent under diagnosis of LS highlights the urgent need for enhanced surveillance and genetic counseling in this demographic. Our findings suggest that adjustments in the current screening protocols may be warranted to better identify and manage at-risk individuals. [ABSTRACT FROM AUTHOR]

Simple Summary: Women at risk of carrying a genetic mutation report higher levels of distress compared to the general population. The aim of this study was to evaluate the mediating role of psychophysical stress in the relationship of anxiety and depression with quality of life and well-being in women undergoing genetic counseling for BRCA1/2 mutations. The results indicate that psychophysical stress, generated by emotional distress, significantly influences the perceived mental well-being and overall psychophysical health. This paper emphasizes the need for integrated care, addressing psychological distress alongside physical health and recognizing the multifaceted impact of hereditary breast cancer screening on patients' overall quality of life and well-being. Background: Women undergoing genetic counseling for hereditary breast cancer often experience a high emotional burden. Distress and stress in the initial phases of genetic counseling can be significant predictors of long-term psychological health, influencing quality of life and well-being. Objectives: This study aimed to evaluate the mediating role of psychophysical stress in the relationship of anxiety and depression with quality of life and well-being in women undergoing genetic counseling for BRCA1/2 mutations. Methods: A sample of 193 women from two genetic counseling clinics was assessed using validated questionnaires measuring the psychological variables under study. Sociodemographic and clinical characteristics were also considered. Results: The results of path analyses indicated a mediating role of psychophysical stress on the relationship between emotional distress and mental quality of life and well-being: higher levels of anxiety and depression were associated with increased psychophysical stress, which, in turn, was linked to a reduced perceived mental quality of life and well-being. Depression was the only significant psychological predictor of physical quality of life. Conclusions: These findings indicate that addressing both anxiety and depression in genetic counseling is crucial for enhancing mental and overall well-being. Interventions should focus on stress management to improve the quality of life, emphasizing depression treatment to enhance physical health outcomes. [ABSTRACT FROM AUTHOR]

Ganciclovir (GCV) is a clinically important drug as it is used to treat viral infections. GCV is incorporated into the DNA during replication, where it interferes with subsequent replication on GCV‐incorporated templates. However, the effects of GCV on the host genome and the mechanisms underlying cellular tolerance to GCV remain unclear. In this study, we explored these mechanisms using a collection of mutant DT40 cells. We identified RAD17/−, BRCA1−/−, and RAD18−/− cells as highly GCV‐sensitive. RAD17, a component of the alternative checkpoint‐clamp loader RAD17‐RFC, was required for the activation of the intra‐S checkpoint following GCV treatment. BRCA1, a critical factor for promoting homologous recombination (HR), was required for suppressing DNA double‐strand breaks (DSBs). Moreover, RAD18, an E3‐ligase involved in DNA repair, was critical in suppressing the aberrant ligation of broken chromosomes caused by GCV. We found that BRCA1 suppresses DSBs through HR‐mediated repair and template switching (TS)‐mediated damage bypass. Moreover, the strong GCV sensitivity of BRCA1−/− cells was rescued by the loss of 53BP1, despite the only partial restoration in the sister chromatid exchange events which are hallmarks of HR. These results indicate that BRCA1 promotes cellular tolerance to GCV through two mechanisms, TS and HR‐mediated repair. [ABSTRACT FROM AUTHOR]

Breast cancer remains a major health threat throughout the world specifically in women above 30 years of age however, it is rarely known to affect men as well. It is characterized by the abnormal division of cells in the breast tissue resulting in the development of breast malignancies. Various risk factors contributing to breast cancer include age, family history, genetic mutations (chiefly in BRCA1 and BRCA2 genes) along with hormonal imbalances (oestrogen, progesterone, HER2). Early detection which can be obtained through frequent rounds of self-examination, mammographic scanning, and clinical assessment plays a crucial role in the prevention of the disease. In addition, appropriate diagnosis assists in better therapeutic responses. This study highlights the considerable health risks associated with the conventional treatment procedures which arise and increased demand of advanced, secure, and risk-free treatment alternatives. Oncolytic viruses are potentially apparent for the aim of improving cancer therapeutics with reduced side effects. These viruses act as the fundamental therapeutic agent themselves that selectively target and kill malignant cells without harm to healthy tissues. The key objective of the research is to provide evidence that Human Adenovirus 52 is a potent oncolytic virus and to highlight its capacity to target and eliminate cancer cells with precision while causing the least amount of harm to healthy tissues. Validating the in-silico method entails evaluating the precision and dependability of the computational modelling by contrasting the in-silico predictions with the findings from the experiments rank as the secondary objective. The workflow of this research utilized in-silico computational drug designing approaches including retrieval of tertiary structures of both the target Breast Cancer Type 1 Susceptibility Protein (BRCA1) and the viral Human Adenovirus 52 protein, their validation generating Ramachandran Plots determining favoured amino acid residue angles and prediction of their active residues. Furthermore, the study focused on the molecular dynamics docking of proteins, interpretation of molecular interactions between the docked complex, as well as the assessment of the molecular dynamic simulations (MD) in addition to their MMGBSA binding energy calculations. A successful docking between BRCA1 and Adenovirus protein provided a significant score of 329.2 +/- 24.3, furthermore, MD simulations showed a high RMSD peak at 2.8 Å, RMSF were maximum at 3.5 Å with highest protein–protein interaction, the radius of gyration was stable throughout the simulation representing elastic stability along with a high energy interaction value of - 7882 kCal/mol. Moreover, the MMGBSA calculation results showed a notable release of binding free energy of - 68.96 kCal/mol demonstrating effective bond formation between the docked complex. These findings propose the effectiveness of Human Adenovirus 52 to treat cancer. The selected oncolytic Human Adenovirus 52 is a potential candidate for the target specific treatment of breast cancer through virotherapy. This computer-aided drug discovery presents significant potential in targeting cancer cells and would assist in the development of potent drug reagents for the cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC. Methods: We enrolled 160 patients with GC in this study. Their tumor samples were subjected to genomic profiling utilizing targeted tumor sequencing. HRD was defined as the presence of alterations in any of 16 HR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, and XRCC2). The clinicopathological features and treatment outcomes of first-line chemotherapy for unresectable metastatic GC were compared between HRD and non-HRD groups. Results: Forty-seven patients (29.4%) were classified into the HRD group. This group had a significantly lower proportion of macroscopic type 3 or 4 tumors and higher TMB than the non-HRD group. Among patients who underwent platinum-based first-line chemotherapy, the HRD group had a greater response rate and longer progression-free survival after treatment (median 8.0 months vs. 3.0 months, P = 0.010), with an adjusted hazard ratio of 0.337 (95% confidence interval 0.151–0.753). HRD status was not associated with treatment outcomes in patients who did not undergo platinum-based chemotherapy. Conclusions: Low proportion of macroscopic type 3 or 4 tumors and a high TMB are distinctive features of GC with HRD. HRD status is a potential predictive marker in platinum-based first-line chemotherapy for unresectable metastatic GC. [ABSTRACT FROM AUTHOR]

Prior studies have suggested the existence of reduced penetrance pathogenic variants (RPPVs) in BRCA1 and BRCA2 (BRCA) which pose challenges for patient counseling and care. Here, we sought to establish RPPVs as a new category of variants. Candidate BRCA RPPVs provided by two large clinical diagnostic laboratories were compiled to identify those with the highest likelihood of being a RPPV, based on concordant interpretations. Sixteen concordant candidate BRCA RPPVs across both laboratories were systematically assessed. RPPVs included missense, splice site, and frameshift variants. Our study establishes RPPVs as a new class of variants imparting a moderately increased risk of breast cancer, which impacts risk-informed cancer prevention strategies, and provides a framework to standardize interpretation and reporting of BRCA RPPVs. Further work to define clinically meaningful risk thresholds and categories for reporting BRCA RPPVs is needed to personalize cancer risks in conjunction with other risk factors. [ABSTRACT FROM AUTHOR]

Background: The incidence of breast cancer remains high and severely affects human health. However, given the heterogeneity of tumor cells, identifying additional characteristics of breast cancer cells is essential for accurate treatment. Purpose: This study aimed to analyze the relevant characteristics of matrix genes in breast cancer through the multigroup data of a breast cancer multi-database. Methods: The related characteristics of matrix genes in breast cancer were analyzed using multigroup data from the breast cancer multi database in the Cancer Genome Atlas, and the differential genes of breast cancer matrix genes were identified using the elastic net penalty logic regression method. The risk characteristics of matrix genes in breast cancer were determined, and matrix gene expression in different breast cancer cells was evaluated using real-time fluorescent quantitative polymerase chain reaction (PCR). A consensus clustering algorithm was used to identify the biological characteristics of the population based on the matrix molecular subtypes in breast cancer, followed by gene mutation, immune correlation, pathway, and ligand-receptor analyses. Results: This study reveals the genetic characteristics of cell matrix related to breast cancer. It is found that 18.1% of stromal genes are related to the prognosis of breast cancer, and these genes are mostly concentrated in the biological Frontiers in processes related to metabolism and cytokines in protein. Five different matrixrelated molecular subtypes were identified by using the algorithm, and it was found that the five molecular subtypes were obviously different in prognosis, immune infiltration, gene mutation and drug-making gene analysis. Conclusions: This study involved analyzing the characteristics of cell-matrix genes in breast cancer, guiding the precise prevention and treatment of the disease. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, despite significant advancements in treatment, remains a major cause of cancer-related deaths among women. Immunotherapy, an emerging therapeutic strategy, offers promise for better outcomes, particularly through the modulation of immune functions. Glioma-Associated Oncogene Homolog 1 (GLI1), a transcription factor implicated in cancer biology, has shown varying roles in different cancers. However, its immunoregulatory functions in breast invasive carcinoma (BRCA) remain elusive. The current study aimed to unravel the expression patterns and immune-regulatory roles of GLI1 in BRCA. Methods: Utilizing multiple bioinformatic platforms (TIMER2.0, GEPIA2, and R packages) based on The Cancer Genome Atlas (TCGA) and/or Genotype-Tissue Expression (GTEx) databases, we analyzed the expression of GLI1 in BRCA and its pan-cancer expression profiles. We further validated these findings by conducting qPCR and immunohistochemical staining on clinical BRCA samples. Kaplan-Meier analysis and Cox proportional hazards regression were performed to assess the prognostic value of GLI1. Additionally, the association between GLI1 expression and immune infiltration within the tumor immune microenvironment (TMIE) was examined. Results: The findings reveal dysregulated expression of GLI1 in numerous cancers, with a significant decrease observed in BRCA. High GLI1 expression indicated better survival outcomes and was correlated with the age and stage of BRCA patients. GLI1 was involved in immune status, as evidenced by its strong correlations with immune and stromal scores and the infiltration levels of multiple immune cells. Meanwhile, GLI1 was co-expressed with multiple immune-related genes, and high GLI1 expression was associated with the activation of immune-related pathways, such as binding to proteasome and mismatch repair and retinol metabolism signaling pathways. Additionally, the differential expression of GLI1 may be related to the effect of immunotherapy on CTLA-4, PD-1, and other signals, and can effectively predict the immune efficacy. Conclusion: Our study underscores the critical role of GLI1 in BRCA, both as a potential tumor suppressor and an immune regulator. The association between GLI1 expression and favorable prognosis suggests its potential as a prognostic biomarker and immunotherapeutic target in BRCA. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer (BC) is a prevailing malignancy among women, and its inconspicuous development contributes significantly to mortality. The RNA N6-methyladenosine (m6A) modification represents an emerging mechanism for gene expression regulation, with the active involvement of the YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) in tumor progression across multiple cancer types. Nonetheless, its precise function in breast cancer necessitates further investigation. Methods: The expression of YTHDF3 in both cell lines and patient tissues was examined using Western blotting, reverse transcription quantitative PCR (RT-qPCR), and immunohistochemistry (IHC) techniques. Bioinformatics analysis of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptome RNA sequencing (RNA-seq) data was employed to screen for the target genes of YTHDF3. The main focus of this study was to investigate the in vitro biological functions of YTHDF3. The specific binding of YTHDF3 to its target genes and its correlation with m6A methylation were studied through RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation experiments. The protein regulatory mechanisms of downstream genes of YTHDF3 were assessed using protein stability analysis. Furthermore, the biological functions of YTHDF3 and its target genes in breast cancer cells were validated through CRISPR-Cas9 technology and rescue experiments. Results: By constructing a risk model using the TCGA database, YTHDF3 was identified as a high-risk factor among m6A methylation factors. Subsequent investigations revealed its elevated expression in various subtypes of breast cancer, accompanied by poor prognosis. MeRIP-seq analysis further revealed fibroblast growth factor 2 (FGF2) as a downstream gene of YTHDF3. Knockdown of YTHDF3 in breast cancer cells led to significant inhibition of cell self-renewal, migration, and invasion abilities in vitro. Mechanistically, YTHDF3 specifically recognized the methylated transcript of FGF2 within its coding sequence (CDS) region, leading to the inhibition of FGF2 protein degradation. Moreover, depletion of FGF2 markedly suppressed the biological functions of breast cancer cells, while reducing FGF2 expression in YTHDF3-overexpressing breast cancer cell lines substantially alleviated the malignant progression. Conclusions: In summary, our study elucidates the role of YTHDF3 as an oncogene in maintaining FGF2 expression in BC cells through anm6A-dependent mechanism. Additionally, we provide a potential biomarker panel for prognostic prediction in BC. [ABSTRACT FROM AUTHOR]

Background:BRCA1 gene dysfunction seen in epithelial ovarian carcinomas often results from germline mutations, somatic mutations, and promoter methylation. Identification of tumors with loss of BRCA1 protein expression has shown to have therapeutic and prognostic implications. The aim of this study was to determine the expression of BRCA1 protein in epithelial ovarian cancer (EOC) and the associated clinicopathological characteristics. Methods and Results: This was a cross‐sectional laboratory‐based study that used paraffin‐embedded tissue blocks of patients histologically diagnosed with EOC from January 2010 to August 2018. Tissue sections were stained with hematoxylin and eosin (H&E) for histological confirmation and with immunohistochemistry (IHC) using a mouse‐derived monoclonal antibody MS110 for BRCA1 protein expression. The association between BRCA1 protein expression and independent variables was determined using Pearson's Chi‐square test. A total of 104 tissue blocks from patients with EOC were included in the study with a mean age of 48.7 ± 12.8 years. Serous tumors were the most common which comprised 74.0% (77/104) of all the tumors and majority of them 75.3% (58/77) were high grade. Loss of expression of BRCA1 protein expression was found in 33.7% (33/98) of all the cases. There was no statistically significant association between BRCA1 expression and age of patients, tumor grade, and histological subtype. Conclusion: There is a high expression of altered BRCA1 expression in tissues of EOC. Although it has not shown association with age of patients, histology types, and tumor grade, further studies need to assess its influence of the survival of cancer patients with EOC. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BrCa) is one of the leading causes of cancer-related deaths. There are several factors for getting BrCa, including some changeable factors related to lifestyle like unhealthy dietary patterns, so modifying them can prevent one third of the complications and deaths caused by BrCa. Therefore, we decided to investigate the relationship between Healthy Beverage Index (HBI) and the risk of BrCa. Methods: In this hospital-based case–control study, 253 patients with BrCa and 267 non-BrCa controls were enrolled. Food consumption was recorded to calculate the HBI score using a semi-quantitative Food Frequency Questionnaire (FFQ). Additionally, by using binary logistic regression analysis with adjustment for confounders, the relationship between HBI and the risk of BrCa were assessed. HBI was established by Duffey et al. and is used to evaluate the overall quality of beverage intake and identify changes in consumption. Results: Mean ± SD of age and BMI of the study participants were 47.92 ± 10.33 years and 29.43 ± 5.51 kg/m2, respectively. Patients with BrCa considerably outperformed controls in terms of waist circumference (WC), age at first pregnancy, history of abortion, and number of children(Pvalue < 0.05). Compared with those in the lowest quartile of HBI, subjects in the highest quartile had higher intake of energy, carbohydrate, protein, fat, fiber, sodium, potassium, calcium, magnesium, zinc, vitamin C, E, B9, fruits, vegetables, fish and nut as well as lower BMI and WC (Pvalue < 0.05). After adjustment for potential confounders, individuals in highest compared to lowest quartile of HBI had significantly lower risk of BrCa for total population (odds ratio (OR): 0.40; 95% confidence interval (95%CI): 0.21–0.76, Pvalue < 0.05), premenopausal (OR: 0.38; 95% CI: 0.16–0.92, Pvalue = 0.013), and postmenopausal (OR: 0.27; 95% CI: 0.10–0.78, Pvalue = 0.023). Conclusion: Findings of this study suggested that higher HBI score decreased the risk of BrCa. However, further investigation is needed. [ABSTRACT FROM AUTHOR]

The p53 is a crucial tumor suppressor and transcription factor that participates in apoptosis and senescence. It can be activated upon DNA damage to regulate the expression of a series of genes. Previous studies have demonstrated that some specific lncRNAs are part of the TP53 regulatory network. To enhance our understanding of the relationship between lncRNAs and P53 in cancers, we review the localization, structure, and function of some lncRNAs that are related to the mechanisms of the p53 pathway or serve as p53 transcriptional targets. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer (BC) is a prevailing malignancy among women, and its inconspicuous development contributes significantly to mortality. The RNA N6-methyladenosine (m6A) modification represents an emerging mechanism for gene expression regulation, with the active involvement of the YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) in tumor progression across multiple cancer types. Nonetheless, its precise function in breast cancer necessitates further investigation. Methods: The expression of YTHDF3 in both cell lines and patient tissues was examined using Western blotting, reverse transcription quantitative PCR (RT-qPCR), and immunohistochemistry (IHC) techniques. Bioinformatics analysis of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptome RNA sequencing (RNA-seq) data was employed to screen for the target genes of YTHDF3. The main focus of this study was to investigate the in vitro biological functions of YTHDF3. The specific binding of YTHDF3 to its target genes and its correlation with m6A methylation were studied through RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation experiments. The protein regulatory mechanisms of downstream genes of YTHDF3 were assessed using protein stability analysis. Furthermore, the biological functions of YTHDF3 and its target genes in breast cancer cells were validated through CRISPR-Cas9 technology and rescue experiments. Results: By constructing a risk model using the TCGA database, YTHDF3 was identified as a high-risk factor among m6A methylation factors. Subsequent investigations revealed its elevated expression in various subtypes of breast cancer, accompanied by poor prognosis. MeRIP-seq analysis further revealed fibroblast growth factor 2 (FGF2) as a downstream gene of YTHDF3. Knockdown of YTHDF3 in breast cancer cells led to significant inhibition of cell self-renewal, migration, and invasion abilities in vitro. Mechanistically, YTHDF3 specifically recognized the methylated transcript of FGF2 within its coding sequence (CDS) region, leading to the inhibition of FGF2 protein degradation. Moreover, depletion of FGF2 markedly suppressed the biological functions of breast cancer cells, while reducing FGF2 expression in YTHDF3-overexpressing breast cancer cell lines substantially alleviated the malignant progression. Conclusions: In summary, our study elucidates the role of YTHDF3 as an oncogene in maintaining FGF2 expression in BC cells through an m6A-dependent mechanism. Additionally, we provide a potential biomarker panel for prognostic prediction in BC. [ABSTRACT FROM AUTHOR]

Copper-induced cell death is regulated through protein lipoylation, which is critical for gene expression and phenotypic regulation. Neverless, the role of Cuproptosis-related genes in breast cancer (BC) remains unknown. This study aimed to construct a prognostic signature based on the expression of Cuproptosis-related genes in order to guide the diagnosis and treatment for BC. Cuproptosis-related genes prognostic signature has ata of 1250 BC tissues and 583 normal breast tissues were obtained from The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), and GEO GSE65212. The prognostic signature was established and evaluated with nineteen Cuproptosis-related genes. A series of in silico analyses based on SLC31A1, included expression analysis, independent prognostic analysis, correlation analysis, immune-related analysis and survival analysis. Finally, a series of cell experiments (including quantitative real-time polymerase chain reaction and western blot), and mice experiments were applied to evaluate the impact of SLC31A1 on BC. Cuproptosis-related genes prognostic signature has good predictive promising for survival in BC patients. We discovered that SLC31A1SLC31A1 was overexpressed in BC and was its independent prognostic factor. High expression of the SLC31A1 was correlated with poor prognosis and immune infiltrating of BC. SLC31A1 expression is associated with immune, chemotherapeutic and targeted therapy outcomes in BC. The proliferation, migration, and invasiveness of Her2 + enriched BC cells were decreased by SLC31A1 knockdown, also resulting in a decrease in tumor volume in mouse model. SLC31A1 is a candidate biomarker or therapeutic target in precision oncology, with diagnostic and prognostic significance in BC. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BrCa) is the most common cancer for women globally. BrCa incidence varies by age and differs between racial groups, with Black women having an earlier age of onset and higher mortality compared to White women. The underlying biological mechanisms of this disparity remain uncertain. Here, we address this knowledge gap by examining the association between overall epigenetic age acceleration and BrCa initiation as well as the mediating role of race. Results: We measured whole-genome methylation (866,238 CpGs) using the Illumina EPIC array in blood DNA extracted from 209 women recruited from University Hospitals Cleveland Medical Center. Overall and intrinsic epigenetic age acceleration was calculated–accounting for the estimated white blood cell distribution–using the second-generation biological clock GrimAge. After quality control, 149 BrCa patients and 42 disease-free controls remained. The overall chronological mean age at BrCa diagnosis was 57.4 ± 11.4 years and nearly one-third of BrCa cases were self-reported Black women (29.5%). When comparing BrCa cases to disease-free controls, GrimAge acceleration was 2.48 years greater (p-value = 0.0056), while intrinsic epigenetic age acceleration was 1.72 years higher (p-value = 0.026) for cases compared to controls. After adjusting for known BrCa risk factors, we observed BrCa risk increased by 14% [odds ratio (OR) = 1.14; 95% CI: 1.05, 1.25] for a one-year increase in GrimAge acceleration. The stratified analysis by self-reported race revealed differing ORs for GrimAge acceleration: White women (OR = 1.17; 95% CI: 1.03, 1.36), and Black women (OR = 1.08; 95% CI: 0.96, 1.23). However, our limited sample size failed to detect a statistically significant interaction for self-reported race (p-value >0.05) when examining GrimAge acceleration with BrCa risk. Conclusions: Our study demonstrated that epigenetic age acceleration is associated with BrCa risk, and the association suggests variation by self-reported race. Although our sample size is limited, these results highlight a potential biological mechanism for BrCa risk and identifies a novel research area of BrCa health disparities requiring further inquiry. [ABSTRACT FROM AUTHOR]

Background: To study BRCA1/2 gene variants in La Rioja in the northcentral area of Spain. Methods: We performed a molecular analysis of BRCA1 and BRCA2 in 642 individuals from 427 different families from June 2008 to December 2019. Results: We identified 71 families with pathogenic variants in these genes, 32 families with BRCA1 variants and 39 families with BRCA2 variants. The pathogenic variants c.959delG in BRCA1 and c.1363_1369delTCAGAGA, c.1397dupA, c.4234_4236delACTinsC and c.8387delC in BRCA2 have not been previously described. The c.81–2 A > T variant in BRCA1, detected in two unrelated families, has not been reported previously in the Spanish population. Two large genomic deletions were found in the BRCA1 gene in exons (Ex) 23–24 and Ex1A-1B-2, and one deletion was found in the BRCA2 gene in Ex2. The pathogenic variant c.5123 C > A in BRCA1 was detected in 8 unrelated families and was the most frequent pathogenic variant in our population. The c.6024dupG mutation in BRCA2 was detected in 6 unrelated families; the c.2808_2011delACAA mutation in BRCA2 was found in 5 different families; the c.211 A > G mutation in BRCA1 was found in three different families; and the c.68_69delAG, c81-2 A > T, c.4038_4039delAA, and c.5266dupC variants in BRCA1 and the c.2457delA, c.2701delC, c.5116_5119delAATA, c.6275delTT, c.7558 C > T and c.7617 + 1G > A variants in BRCA2 were found in two different families. Conclusions: The spectrum of pathogenic variants in the BRCA1/2 genes in La Rioja is similar to that in other Spanish regions, with some unique characteristics. The pathogenic c.6024dupG variant in the BRCA2 gene was detected in a large number of families and could have a founding effect in the Ebro riverside areas in the regions of La Rioja and Navarra. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Objective: Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib and niraparib have shown promise in extending progression-free survival (PFS) in patients with platinum-sensitive recurrent (PSR) epithelial ovarian cancer. In this retrospective study, we aimed to present our own data on the effect of PARP inhibitors on PFS in recurrent epithelial ovarian cancer. Methods: 82 patients diagnosed with PSR epithelial ovarian, tubal, or primary peritoneal cancer between May 2017 and September 2023 were initially enrolled from our hospital. However, 16 patients had prior exposure to PARP inhibitors during primary treatment, and 11 were lost to follow-up. Consequently, the study focused on 55 eligible patients. PFS was compared between patients receiving PARP inhibitor maintenance therapy and those who did not. Results: Among the 55 patients with PSR epithelial ovarian cancer, 18 received olaparib as maintenance therapy, 19 received niraparib, and 18 opted for observation. PARP inhibitor therapy significantly extended PFS (mean 24.0 months) compared to observation (mean 9.0 months, p = 0.0005), regardless of BRCA mutation status (HR = 0.20, 95% CI: 0.08–0.50). Subgroup analysis showed no statistical difference between olaparib and niraparib. Additionally, there was no PFS difference based on BRCA mutation status within both PARP inhibitor groups. Conclusion: Our retrospective study demonstrates that PARP inhibitor maintenance therapy, including olaparib and niraparib, significantly prolongs PFS in patients with PSR epithelial ovarian, tubal, or primary peritoneal cancer, These findings support the broad utilization of PARP inhibitors as a standard maintenance therapy for PSR epithelial ovarian cancer irrespective of BRCA mutation status. Summary: PARP inhibitor maintenance therapy, including olaparib and niraparib, significantly prolongs PFS in patients with PSR epithelial ovarian, tubal, or primary peritoneal cancer, irrespective of BRCA mutation status. PARP inhibitors can be recommended as a standard maintenance therapy for PSR epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Triple‐negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. This study is aimed at identifying potential therapeutic targets in TNBC using gene regulatory network analysis and a system biology approach. Methods: The GSE38959 dataset was reanalyzed to identify differentially expressed genes (DEGs) in TNBC tissues compared to normal breast samples. Protein–protein interaction networks were constructed, and hub genes were identified. Survival analysis was performed using GEPIA2. Gene regulatory networks were built to identify upstream regulators. Cross‐platform verification was conducted using an independent RNA‐seq dataset (GSE58135). Expression analysis of prognostic markers in TNBC versus non‐TNBC samples was performed using bc‐GenExMiner. Results: A total of 943 DEGs were identified in TNBC tissues. CHEK1 and PLK1 were identified as central hub genes, with overexpression correlating with poor prognosis. GABPB1 was identified as the most influential upstream regulator of CHEK1 and PLK1 through gene regulatory network analysis, while JUN exhibited the most interactions among regulators. A total of 302 consistently modulated genes were confirmed through cross‐platform verification. The overexpression of CHEK1 and PLK1 in TNBC compared to non‐TNBC samples was validated by expression analysis. Conclusion: This study provides insights into the molecular mechanisms of TNBC and suggests CHEK1, PLK1, and their upstream regulators as potential therapeutic targets for TNBC treatment. [ABSTRACT FROM AUTHOR]

The prevalence of malignant cells in clinical specimens, or tumour purity, is affected by both intrinsic biological factors and extrinsic sampling bias. Molecular characterization of large clinical cohorts is typically performed on bulk samples; data analysis and interpretation can be biased by tumour purity variability. Transcription-based strategies to estimate tumour purity have been proposed, but no breast cancer specific method is available yet. We interrogated over 6000 expression profiles from 10 breast cancer datasets to develop and validate a 9-gene Breast Cancer Purity Score (BCPS). BCPS outperformed existing methods for estimating tumour content. Adjusting transcriptomic profiles using the BCPS reduces sampling bias and aids data interpretation. BCPS-estimated tumour purity improved prognostication in luminal breast cancer, correlated with pathologic complete response in on-treatment biopsies from triple-negative breast cancer patients undergoing neoadjuvant treatment and effectively stratified the risk of relapse in HER2+ residual disease post-neoadjuvant treatment. [ABSTRACT FROM AUTHOR]

Deep learning models for predicting variant pathogenicity have not been thoroughly evaluated on real-world clinical phenotypes. Here, we apply state-of-the-art pathogenicity prediction models to hereditary breast cancer gene variants in UK Biobank participants. Model predictions for missense variants in BRCA1, BRCA2 and PALB2, but not ATM and CHEK2, were associated with breast cancer risk. However, deep learning models had limited clinical utility when specifically applied to variants of uncertain significance. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence has indicated possible efficacy benefit of platinum‐based chemotherapy as neoadjuvant treatment for invasive ductal carcinoma triple‐negative breast cancer (TNBC). However, it has not been endorsed by current guidelines due to highly controversial results. Materials and Methods: Present study aims to investigate predictive and prognostic roles concerning single nucleotide polymorphisms (SNPs) in XRCC1 and BRCA1, BRCA2 genes for early stage TNBC patients that received platinum‐based neoadjuvant treatment. We prospectively enrolled women with stage IIB‐IIIB TNBC that had progressed on neoadjuvant taxane and anthracycline‐based chemotherapy at Xinjiang Medical University Affiliated Cancer Hospital. Tumor response and pathological complete response (pCR) rate were assessed. Invasive disease‐free survival (iDFS) and overall survival (OS) were analyzed. Patients' blood samples were subject to Sanger sequencing to genotype XRCC1 Arg194Trp and Arg399Gln, BRCA1 s1799949, and BRCA2 rs206115. Univariate and multivariate logistic regressions were employed to investigate associations between SNPs and clinical characteristics with treatment response and pCR. A total of 45 patients were enrolled. Results: The cohort showcased ORR of 44.4%, pCR of 28.9%, median iDFS of 22 months, and a 3‐year OS of 73.3%. The A/G and G/G genotypes of BRCA1 rs1799949, and the T/T genotype of BRCA2 rs206115 were associated with higher responsive rate. Histologic grade of III and Ki67 expression > 65% were associated with low responsive rate. Moreover, the A/G genotype of BRCA1 rs1799949 and T/T genotype of BRCA2 rs206115 correlated to high pCR. The histologic III and T4 stage correlated to inferior iDFS. Carrier of BRCA1 rs1799949 G/G had the most favorable OS, carriers of A/A showed the poorest OS, and those with A/G genotype showed an intermediate OS. Conclusions: Platinum‐based chemotherapy might serve as a therapeutic option for TNBC patients who were resistant to anthracycline‐ and taxane‐based neoadjuvant therapy. Our study identified several genetic and clinical features that might function as prognostic and predictive markers. [ABSTRACT FROM AUTHOR]

Simple Summary: The anticancer activity of PARP inhibitors in pancreatic cancer with mutations in HRR genes other than BRCA and PALB2 remains inconclusive. The authors retrospectively reviewed the clinical characteristics and outcomes of patients with advanced pancreatic cancer harboring pathogenic germline and/or somatic HRR mutations who were treated with PARP inhibitors. PARP inhibitors may be considered for patients with advanced pancreatic cancer harboring pathogenic alterations of BRCA who cannot tolerate standard chemotherapy. Maintenance PARP inhibitor therapy may be considered in selected patients with non-BRCA and non-PALB2 HRR mutations. Background: Limited data are available regarding the anticancer activity of PARP inhibitors (PARPis) in pancreatic cancer with mutations in HRR genes other than BRCA and PALB2. Methods: We retrospectively reviewed the clinical characteristics and outcomes of 48 patients with advanced pancreatic cancer harboring pathogenic germline and/or somatic HRR mutations who were treated with PARPis. Results: Thirty patients had germline (g)HRR mutations only, twelve had somatic (s)HRR mutations only, and six had concomitant gHRR and sHRR mutations. The objective response rate (ORR) was 22%. The median progression-free survival (mPFS) and overall survival (mOS) were 6.9 and 11.5 months, respectively. Five patients received olaparib in the front-line setting due to borderline performance status. Their ORR was 20%, and their mPFS and mOS were both 11.3 months. The ORR was higher in patients with BRCA or PALB2 mutations (germline or somatic) than in those with non-BRCA/PALB2 mutations. Patients with somatic non-BRCA/PALB2 variants had a shorter mPFS. Patients with concomitant gHRR/sHRR mutations or gHRR mutations alone had a significantly longer mPFS than those with sHRR mutations only. Conclusions: PARP inhibitors may be considered for patients with advanced pancreatic cancer harboring pathogenic alterations of BRCA who cannot tolerate standard chemotherapy. Maintenance PARPis can be considered in selected patients with non-BRCA/non-PALB2 HRR mutations. [ABSTRACT FROM AUTHOR]

Interleukins play dual roles in breast cancer, acting as both promoters and inhibitors of tumorigenesis within the tumor microenvironment, shaped by their inflammatory functions. This study analyzed the subtype-specific prognostic significance of an acute inflammatory versus a chronic inflammatory interleukin signature using microarray-based gene expression analysis. Correlations between these interleukin signatures and immune cell markers (CD8, IgKC, and CD20) and immune checkpoints (PD-1) were also evaluated. This study investigated the prognostic significance of an acute inflammatory IL signature (IL-12, IL-21, and IFN-γ) and a chronic inflammatory IL signature (IL-4, IL-5, IL-10, IL-13, IL-17, and CXCL1) for metastasis-free survival (MFS) using Kaplan–Meier curves and Cox regression analyses in a cohort of 461 patients with early breast cancer. Correlations were analyzed using the Spearman–Rho correlation coefficient. Kaplan–Meier curves revealed that the prognostic significance of the acute inflammatory IL signature was specifically pronounced in the basal-like subtype (p = 0.004, Log Rank). This signature retained independent prognostic significance in multivariate Cox regression analysis (HR 0.463, 95% CI 0.290–0.741; p = 0.001). A higher expression of the acute inflammatory IL signature was associated with longer MFS. The chronic inflammatory IL signature showed a significant prognostic effect in the whole cohort, with higher expression associated with shorter MFS (p = 0.034). Strong correlations were found between the acute inflammatory IL signature and CD8 expression (ρ = 0.391; p < 0.001) and between the chronic inflammatory IL signature and PD-1 expression (ρ = 0.627; p < 0.001). This study highlights the complex interaction between acute and chronic inflammatory interleukins in breast cancer progression and prognosis. These findings provide insight into the prognostic relevance of interleukin expression patterns in breast cancer and may inform future therapeutic strategies targeting the immune–inflammatory axis. [ABSTRACT FROM AUTHOR]

Background: Few studies have explored the expression profile of RPL3 in breast cancer (BRCA). Our research provided an in-depth analysis of RPL3 expression patterns in BRCA, highlighting its significance for therapy prediction and prognosis. Methods: RPL3 was notably elevated in malignant cells, and its expression level was closely associated with tumor size and overall survival outcomes. Our study also identified RPL3-related terms and pathways and revealed a strong correlation between RPL3 expression and breast carcinoma immunity, demonstrating inconsistent expression levels in various immune cell lines. In addition, we examined the relationship between RPL3 expression and tumor mutational burden (TMB) in BRCA. To assess the clinical implications of BRCA chemotherapy, we investigated the correlation between RPL3 expression levels and drug sensitivity. Results: Our findings suggest that RPL3 plays a critical role in the BRCA process and is associated with immune infiltration, indicating its potential as a novel immunotherapy target in BRCA treatment. Conclusions: In summary, our research underscores the importance of RPL3 expression levels in tumorigenesis and its potential for guiding BRCA immunotherapy. [ABSTRACT FROM AUTHOR]

Cochlear hair cells (HCs) sense sound waves and allow us to hear. Loss of HCs will cause irreversible sensorineural hearing loss. It is well known that DNA damage repair plays a critical role in protecting cells in many organs. However, how HCs respond to DNA damage and how defective DNA damage repair contributes to hearing loss remain elusive. In this study, we showed that cisplatin induced DNA damage in outer hair cells (OHCs) and promoted OHC loss, leading to hearing loss in mice of either sex. Cisplatin induced the expression of Brca1, a DNA damage repair factor, in OHCs. Deficiency of Brca1 induced OHC and hearing loss, and further promoted cisplatin-induced DNA damage in OHCs, accelerating OHC loss. This study provides the first in vivo evidence demonstrating that cisplatin mainly induces DNA damage in OHCs and that BRCA1 promotes repair of DNA damage in OHCs and prevents hearing loss. Our findings not only demonstrate that DNA damage-inducing agent generates DNA damage in postmitotic HCs but also suggest that DNA repair factors, like BRCA1, protect postmitotic HCs from DNA damage-induced cell death and hearing loss. [ABSTRACT FROM AUTHOR]

Background: Recent studies have highlighted the importance of the cell-free DNA (cfDNA) methylation profile in detecting breast cancer (BC) and its different subtypes. We investigated whether plasma cfDNA methylation, using cell-free Methylated DNA Immunoprecipitation and High-Throughput Sequencing (cfMeDIP-seq), may be informative in characterizing breast cancer in patients with BRCA1/2 germline mutations for early cancer detection and response to therapy. Methods: We enrolled 23 BC patients with germline mutation of BRCA1 and BRCA2 genes, 19 healthy controls without BRCA1/2 mutation, and two healthy individuals who carried BRCA1/2 mutations. Blood samples were collected for all study subjects at the diagnosis, and plasma was isolated by centrifugation. Cell-free DNA was extracted from 1 mL of plasma, and cfMeDIP-seq was performed for each sample. Shallow whole genome sequencing was performed on the immuno-precipitated samples. Then, the differentially methylated 300-bp regions (DMRs) between 25 BRCA germline mutation carriers and 19 non-carriers were identified. DMRs were compared with tumor-specific regions from public datasets to perform an unbiased analysis. Finally, two statistical classifiers were trained based on the GLMnet and random forest model to evaluate if the identified DMRs could discriminate BRCA-positive from healthy samples. Results: We identified 7,095 hypermethylated and 212 hypomethylated regions in 25 BRCA germline mutation carriers compared to 19 controls. These regions discriminate tumors from healthy samples with high accuracy and sensitivity. We show that the circulating tumor DNA of BRCA1/2 mutant breast cancers is characterized by the hypomethylation of genes involved in DNA repair and cell cycle. We uncovered the TFs associated with these DRMs and identified that proteins of the Erythroblast Transformation Specific (ETS) family are particularly active in the hypermethylated regions. Finally, we assessed that these regions could discriminate between BRCA positives from healthy samples with an AUC of 0.95, a sensitivity of 88%, and a specificity of 94.74%. Conclusions: Our study emphasizes the importance of tumor cell-derived DNA methylation in BC, reporting a different methylation profile between patients carrying mutations in BRCA1, BRCA2, and wild-type controls. Our minimally invasive approach could allow early cancer diagnosis, assessment of minimal residual disease, and monitoring of response to therapy. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most common tumor in men globally. Its etiology has been attributed to multiple factors, including age and ethnicity, with family history identified as a significant risk factor. The role of family history in prostate cancer risk appears to be more extensive than previously thought, with evidence suggesting that prostate cancer and breast cancer may occur concurrently within families. BRCA2 mutations have been linked to an increased risk of prostate cancer, particularly in patients diagnosed with earlyonset disease. It is estimated that BRCA2 mutations account for approximately 5% of familial prostate cancer cases. It is noteworthy that cases of prostate cancer in patients with BRCA2 mutations are rare in clinical practice. Here we report a case of prostatitis carcinoma with a mutation in the BRCA2 gene in a patient who underwent robotic-assisted radical prostatectomy for prostatitis carcinoma after medication was not effective. Genetic testing of him, his son, and his daughter showed that they all had mutations in this gene, and it is noteworthy that the type of BRCA2 mutation in his son has never been reported before, which is rare in clinical practice. [ABSTRACT FROM AUTHOR]

The article explores candidate-gene studies in pharmacogenomics/pharmacogenetics, focusing on drug effectiveness and safety. It stresses the importance of well-planned studies to yield reliable insights and discusses methodological concepts like causality and confounders. The text also addresses challenges like small sample sizes and limitations of meta-analyses, providing resources for conducting health sciences research and guidelines for gene-drug interactions in cancer treatment. These resources aim to improve the quality and precision of research in the health sciences field. [Extracted from the article]

Background: The identification of women at high risk of breast cancer (BC) is crucial for personalized screening strategies. Pathogenic and likely pathogenic variants (PVs/LPVs) in susceptibility risk genes explain part of the individual risk. Moreover, a polygenic background, summarized as a polygenic risk score (PRS), contributes to the risk of BC and may modify the individual risk in carrier and non-carrier members of BC families. Methods: We performed a retrospective pilot study evaluating PRS in women from a subset of high- (BRCA1 and BRCA2) and moderate-risk (PALB2 and ATM) BC families. We included PVs/LPVs carriers and non-carriers and evaluated a PRS based on 577,113 BC-associated variants. Using BOADICEA, we calculated the adjusted lifetime BC risk. Results: Our data showed that in BRCA1/BRCA2 carriers, PVs have a major role in stratifying the lifetime risk, while PRS improves risk estimation in non-carriers of these families. A different scenario may be observed in PALB2 and ATM families where PRS combined with PV/LPV carrier status gives a more informative lifetime risk. Conclusions: This study showed that in BC families, the PRS might help to quantify the weight of the genetic familial background, improving the individual risk stratification and contributing to personalized clinical management for carrier and non-carrier women. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is categorized into four main intrinsic subtypes, and distinguishing between these subtypes is crucial for providing personalized treatment to patients. However, systematic analyses exploring the connections between gene expression and chromatin accessibility using bulk RNA-seq and ATAC-seq data, coupled with machine learning algorithms, are lacking. In this study, we develop a classification model based on the integrative analysis of RNA-seq transcriptome and ATAC-seq epigenetic information. We identify 10 signature genes associated with these intrinsic subtypes, which are predominantly linked to immune responses, hormone signaling, cancer progression, and cellular proliferation. Breast cancer is a heterogeneous disease composed of various biologically distinct subtypes, each characterized by unique molecular features. Its formation and progression involve a complex, multistep process that includes the accumulation of numerous genetic and epigenetic alterations. Although integrating RNA-seq transcriptome data with ATAC-seq epigenetic information provides a more comprehensive understanding of gene regulation and its impact across different conditions, no classification model has yet been developed for breast cancer intrinsic subtypes based on such integrative analyses. In this study, we employed machine learning algorithms to predict intrinsic subtypes through the integrative analysis of ATAC-seq and RNA-seq data. We identified 10 signature genes (CDH3, ERBB2, TYMS, GREB1, OSR1, MYBL2, FAM83D, ESR1, FOXC1, and NAT1) using recursive feature elimination with cross-validation (RFECV) and a support vector machine (SVM) based on SHAP (SHapley Additive exPlanations) feature importance. Furthermore, we found that these genes were primarily associated with immune responses, hormone signaling, cancer progression, and cellular proliferation. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Ruqyah Shar'iyyah, one of the complementary and alternative medicine (CAM) has shown therapeutic benefits in breast cancer by utilizing Quranic verses in reducing symptoms and enhancing their quality of life as a result of invasive standard therapies. However, scientific evidence is required to demonstrate Ruqyah Shar'iyyah's effectiveness on gene expression and molecular pathways in carcinogenesis. Therefore, this study was conducted to evaluate the effectiveness of Ruqyah Shar'iyyah on breast cancer cell line on apoptosis and CCND1 expression in related signaling pathways. MATERIALS AND METHODS: MCF-7 cell lines were treated with direct recitation of several Quranic verses for 12 hours and 24 hours. Cell viability was observed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of CCND1 was determined using RT-qPCR technique. The molecular mechanism and signalling pathways were evaluated using Reactome database for in silico analysis. RESULTS: Cell viability data showed 95.69% and 93.54% exhibiting slight reduction for 12-hour treatment in untreated and treated MCF-7, respectively. Meanwhile more reduction was observed in 24-hour treatment with 95.11% in untreated cell line as compared to 92.34% in treated cell line. The cell morphology also exhibited apoptotic activity in the treated group for both two time points. Gene expression analysis of CCNDI also demonstrated upregulation with 1.81-fold change. The data was supported by the in-silico analysis in which 25 relevant significant signalling pathways related to CCND1 highlighting the role of the gene in breast cancer development. CONCLUSION: CCND1 may have a function in signalling pathways that control the proliferation of mammary epithelial cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Pathogenic variants in the PALB2 gene significantly increase the risk of developing breast, ovarian, and pancreatic cancers. However, the prevalence of these mutations in East Asian populations, particularly Koreans, has not been well studied. This research aims to estimate the prevalence of PALB2 variants in these populations by analyzing large-scale genomic databases. Understanding the frequency of PALB2 variants can help in identifying individuals at higher risk for these cancers and guide the development of targeted screening and prevention strategies. The findings from this study provide valuable reference data that can enhance genetic counseling and improve cancer risk management in East Asian populations, ultimately contributing to better health outcomes in these communities. PALB2 is a tumor suppressor gene. Heterozygous germline pathogenic variants of PALB2 significantly increase the lifetime risk of breast cancer and moderately increase the risk of ovarian and pancreatic cancers. This study analyzed the estimated prevalence of PALB2 variants globally, focusing on East Asian and Korean populations, where limited data were previously available. We examined 125,748 exomes from the Genome Aggregation Database (gnomAD), including 9197 East Asians, and additional data from 5305 individuals in the Korean Variant Archive and 1722 in the Korean Reference Genome Database. All PALB2 variants were interpreted according to guidelines from the American College of Medical Genetics and Genomics and the Clinical Genome Resource. The global prevalence of PALB2 variants was 0.18%, with the highest prevalence in Finnish populations (0.41%) and the lowest in Ashkenazi Jewish populations (0.04%). East Asians had a prevalence of 0.09%. By combining data from Korean genome databases and gnomAD totaling 8936 individuals, the overall prevalence of PALB2 variants in the Korean population was determined to be 0.13%. This study is the first comprehensive investigation of PALB2 variant prevalence in East Asians and Koreans using gnomAD and Korean genome databases. These findings provide essential reference data for future research and highlight the importance of region-specific genetic studies that will inform genetic counseling and hereditary cancer risk management. [ABSTRACT FROM AUTHOR]

Simple Summary: DNA-dependent protein kinase (DNA-PK) is a key player in repairing DNA damage. Ku proteins detect DNA damage and activate DNA-PK. Blocking DNA-PK can make cancer treatments such as radiation more effective. We have developed Ku–DNA binding inhibitors (Ku-DBis) that stop DNA-PK activation, making cancer cells more sensitive to radiation. We recently discovered new Ku-DBis that enter cells better than predecessor compounds, allowing cellular and in vivo analyses. Some non-small cell lung cancer (NSCLC) cells, especially those lacking ATM, were very sensitive to these inhibitors and radiation. However, cells lacking BRCA1 were resistant, which reduced the effectiveness of radiation. In animal studies of NSCLC, Ku-DBi treatment inhibited DNA-PK and enhanced a radiation-dependent decrease in tumor cell proliferation. This is the first time a Ku-targeted inhibitor has been shown to work in living organisms, suggesting their potential application in cancer treatment. Background: DNA-dependent protein kinase (DNA-PK) is a validated cancer therapeutic target involved in DNA damage response (DDR) and non-homologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs). Ku serves as a sensor of DSBs by binding to DNA ends and activating DNA-PK. Inhibition of DNA-PK is a common strategy to block DSB repair and improve efficacy of ionizing radiation (IR) therapy and radiomimetic drug therapies. We have previously developed Ku–DNA binding inhibitors (Ku-DBis) that block in vitro and cellular NHEJ activity, abrogate DNA-PK autophosphorylation, and potentiate cellular sensitivity to IR. Results and Conclusions: Here we report the discovery of oxindole Ku-DBis with improved cellular uptake and retained potent Ku-inhibitory activity. Variable monotherapy activity was observed in a panel of non-small cell lung cancer (NSCLC) cell lines, with ATM-null cells being the most sensitive and showing synergy with IR. BRCA1-deficient cells were resistant to single-agent treatment and antagonistic when combined with DSB-generating therapies. In vivo studies in an NSCLC xenograft model demonstrated that the Ku-DBi treatment blocked IR-dependent DNA-PKcs autophosphorylation, modulated DDR, and reduced tumor cell proliferation. This represents the first in vivo demonstration of a Ku-targeted DNA-binding inhibitor impacting IR response and highlights the potential therapeutic utility of Ku-DBis for cancer treatment. [ABSTRACT FROM AUTHOR]

Previous studies have shown cord-blood DNA methylation differences in newborns conceived using assisted reproductive technologies (ART) compared to those conceived naturally. However, whether these ART-related DNA methylation differences vary with children's sex is unknown. We hypothesize that the DNA methylation differences in cord blood between ART-conceived and naturally conceived newborns also varies by the sex of the child, with distinct patterns of differential methylation present in males and females. We investigated sex differences in cord-blood DNA methylation variation according to conception by ART using the Illumina MethylationEPIC platform, comparing 456 ART-conceived versus 507 naturally-conceived girls, and 503 ART-conceived and 473 naturally-conceived boys. We identified 37 differentially methylated CpGs according to ART-conception among girls, and 70 differentially methylated CpGs according to ART-conception among boys, when we used a 1% false discovery rate to account for multiple testing. Ten CpGs were differentially methylated according to conception by ART in both sexes. Among the genes that were associated with these CpGs, we found the BRCA1; NBR2 gene (two CpGs) was hypermethylated in girls while the APC2 (two CpGs) and NECAB3;ACTL10, (four CpGs) related to cellular signaling were hypomethylated in boys. These findings confirm the presence of sex-specific epigenetic differences, illustrating the nuanced impact of ART on the fetal epigenome. There is a need for further explorations into the implications for sex-specific developmental trajectories and health outcomes in ART-conceived children. [ABSTRACT FROM AUTHOR]

The tumor immune microenvironment (TIME) plays key roles in tumor progression and response to immunotherapy. Previous studies have identified individual germline variants associated with differences in TIME. Here, we hypothesize that common variants associated with breast cancer risk or cancer-related traits, represented by polygenic risk scores (PRSs), may jointly influence immune features in TIME. We derived 154 immune traits from bulk gene expression profiles of 764 breast tumors and 598 adjacent normal tissue samples from 825 individuals with breast cancer in the Nurses' Health Study (NHS) and NHSII. Immunohistochemical staining of four immune cell markers were available for a subset of 205 individuals. Germline PRSs were calculated for 16 different traits including breast cancer, autoimmune diseases, type 2 diabetes, ages at menarche and menopause, body mass index (BMI), BMI-adjusted waist-to-hip ratio, alcohol intake, and tobacco smoking. Overall, we identified 44 associations between germline PRSs and immune traits at false discovery rate q < 0.25, including 3 associations with q < 0.05. We observed consistent inverse associations of inflammatory bowel disease (IBD) and Crohn disease (CD) PRSs with interferon signaling and STAT1 scores in breast tumor and adjacent normal tissue; these associations were replicated in a Norwegian cohort. Inverse associations were also consistently observed for IBD PRS and B cell abundance in normal tissue. We also observed positive associations between CD PRS and endothelial cell abundance in tumor. Our findings suggest that the genetic mechanisms that influence immune-related diseases are also associated with TIME in breast cancer. We investigated the germline genetic determinants of immune features in the breast tumor microenvironment. Our results reveal genetic links between tumor immune profiles, especially those related to interferon signaling, and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Multilocus inherited neoplasia allelic syndrome (MINAS) is a recently coined term that describes the coexistence of two or more pathogenic variants (PVs) in cancer susceptibility genes (CSGs) in a single individual. Case presentation: This article presents two cases of MINAS due to rare CSG combinations. The first was a 37-year-old woman carrying PVs in the mutated ataxia telangiectasia (ATM) and CHEK2 genes, with HER-2 positive unilateral breast cancer at 29. The second was a 53-year-old woman carrying PVs in the BRCA1 and CDKN2A genes, who presented with triple-negative breast cancer at 51. We describe their family history and treatment, where the lack of evidence for personalised management becomes evident. Conclusion: Predicting the phenotypic effect of harbouring two variants in CSG is challenging. It is essential to encourage the notification of other cases and carry out functional studies to establish specific risks for affected individuals to develop personalised follow-up guidelines to reduce the associated morbimortality. [ABSTRACT FROM AUTHOR]

Purpose: The aim was to assess the diagnostic yield of next generation sequencing (NGS) multi-gene panels for breast and ovarian cancer in a high-complexity cancer centre in Chile. Additionally, our goal was to broaden the genotypic spectrum of BRCA variants already identified in Chilean families. Methods: Retrospective analysis was conducted on the genetic test results of 722 individuals from Fundación Arturo López Pérez's genetic counselling unit between 2016 and 2021. A comprehensive literature review encompassing articles analysing the frequency of germinal pathogenic variants in BRCA1/2 within the Chilean population was undertaken. Results: 23.5% of the panels had positive results, with 60% due to pathogenic variants in the BRCA1/2 genes. Seven previously unreported variants in BRCA1 from Chilean studies were identified. Conclusion: Our findings advocate for the integration of NGS multi-gene panel testing as a primary strategy within our population. This approach allows for the comprehensive assessment of single nucleotide variants and CNVs in BRCA1/2, alongside other high and moderately penetrant genes associated with breast and ovarian cancer. [ABSTRACT FROM AUTHOR]

The singular BRCA1/2 mutational landscape of Asturias is updated 10 years after the first study. We analyzed BRCA1 and BRCA2 pathogenic variants in 1653 index cases. In total, 238 families were identified to carry a pathogenic variant, 163 families in BRCA1 and 75 families in BRCA2. This yielded a prevalence rate of 14.4%. Seven recurrent variants were found accounting for 55% of the cases. Among them, three are widely distributed (BRCA1 c.211A>G, c.470_471del and c.3331_3334del) and four had been reported as novel in Asturias: two in BRCA1 (c.1674del and c.2901_2902dup) and two in BRCA2 (c.2095C>T and c.4040_4035delinsC). A common haplotype was established for all recurrent variants indicating a shared ancestral origin. Three splicing analyses are shown: BRCA1:c.5152+3A>C and BRCA1:c.5333‐3T>G that lead to skipping of exon 18, and 22 respectively, and BRCA1:c.5278‐1G>T giving rise to two transcripts, one lacking exon 21 (p.Ille1760Glyfs*60) and one lacking the first 8 nucleotides of exon 21 (p.Phe1761Asnfs*14), supporting pathogenicity for these variants. [ABSTRACT FROM AUTHOR]

The majority of tumor comprehensive genomic profiling (CGP) currently does not include a matched normal control. The use of a tumor-only CGP approach needs the development of a strategy to refine germline pathogenic/likely pathogenic variants (gP/LPVs) calls, so as to limit the performance of unnecessary germline reflex tests and instead successfully identify patients who are carriers of likely gP/LPVs. Guidelines have been developed for the identification of gP/LPVs in BRCA1/2 genes on the basis of tumor-only CGP results and for the evaluation of the appropriateness of performing germline reflex BRCA1/2 testing. In this study, an algorithm to assist decision-making for germline reflex testing of BRCA1/2 variants following tumor-only CGP is proposed. [ABSTRACT FROM AUTHOR]

Background: Determining the status of breast cancer susceptibility genes (BRCA) is crucial for guiding breast cancer treatment. Nevertheless, the need for BRCA genetic testing among breast cancer patients remains unmet due to high costs and limited resources. This study aimed to develop a Bi-directional Self-Attention Multiple Instance Learning (BiAMIL) algorithm to detect BRCA status from hematoxylin and eosin (H&E) pathological images. Methods: A total of 319 histopathological slides from 254 breast cancer patients were included, comprising two dependent cohorts. Following image pre-processing, 633,484 tumor tiles from the training dataset were employed to train the self-developed deep-learning model. The performance of the network was evaluated in the internal and external test sets. Results: BiAMIL achieved AUC values of 0.819 (95% CI [0.673–0.965]) in the internal test set, and 0.817 (95% CI [0.712–0.923]) in the external test set. To explore the relationship between BRCA status and interpretable morphological features in pathological images, we utilized Class Activation Mapping (CAM) technique and cluster analysis to investigate the connections between BRCA gene mutation status and tissue and cell features. Significantly, we observed that tumor-infiltrating lymphocytes and the morphological characteristics of tumor cells appeared to be potential features associated with BRCA status. Conclusions: An interpretable deep neural network model based on the attention mechanism was developed to predict the BRCA status in breast cancer. Keywords: Breast cancer, BRCA, deep learning, self-attention, interpretability. [ABSTRACT FROM AUTHOR]

Introduction and purpose Individuals with BRCA1 and BRCA2 mutations face significantly heightened likelihood of developing breast and ovarian cancers. Besides some lifestyle recommendations, like maintaining physical activity, healthy BMI, possibly early parenthood and breastfeeding, the management of BRCA1/2 mutation carriers includes gene mutation early-detection, screening, risk-reducing surgeries, and chemoprevention. Various prevention strategies exist, all aimed at monitoring patients and mitigating the cancer risks. However, even with the existence of national and international guidelines to direct prevention efforts, there is no ideal protocol that would be universally applicable for all individuals with mutated BRCA gene. This article aims to delve into the currently available surveillance and preventive strategies and explore the potential future avenues for early detection and risk reduction in BRCA mutation carriers. Materials and methods This study is a literature review based on publications on PubMed using key words: BRCA mutation, breast cancer, ovarian cancer, cancer prevention, surveillance, screening. Description of the State of Knowledge Women identified with BRCA1/BRCA2 mutation are at higher life-time risk of developing breast and ovarian cancer than the general population. Regular screening of breasts and reproductive organs is crucial for managing BRCA germline mutation carriers. There are no preventive medications registered to diminish the endangerment of malignancy. Surgical interventions, such as prophylactic mastectomy and prophylactic salpingo-oophorectomy are preventive measures that significantly mitigate the likelihood of cancer development. Conclusion In consideration of the research discussed, it is imperative that contemporary risk-minimizing strategies for individuals with BRCA gene variation should be customized according to the age of mutation identification, reproductive plans, family history of carcinoma occurrence, and the patient's medical background. Relying solely on surveillance methods may not always be sufficient in managing high-risk patients such as BRCA1/2 carriers. Despite the compelling evidence supporting the effectiveness of risk-reducing surgeries for ovarian and breast cancers, some patients harbor reservations about undergoing procedures that undoubtedly entail potential side effects. The pressing need for alternative non-surgical approaches has prompted increased attention to chemoprevention possibilities. Ongoing research endeavors offer hope for advancements and aim to diversify the range of preventive strategies available for BRCA mutation carriers in the future. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to predict gene signatures in breast cancer patients using multiple machine learning models. Methods: In this study, we first collated and merged the datasets GSE54002 and GSE22820, obtaining a gene expression matrix comprising 16,820 genes (including 593 breast cancer (BC) samples and 26 normal control (NC) samples). Subsequently, we performed enrichment analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO). Results: We identified 177 differentially expressed genes (DEGs), including 40 up-regulated and 137 down-regulated genes, through differential expression analysis. The GO enrichment results indicated that these genes are primarily involved in extracellular matrix organization, positive regulation of nervous system development, collagen-containing extracellular matrix, heparin binding, glycosaminoglycan binding, and Wnt protein binding, among others. KEGG enrichment analysis revealed that the DEGs were primarily associated with pathways such as focal adhesion, the PI3K–Akt signaling pathway, and human papillomavirus infection. DO enrichment analysis showed that the DEGs play a significant role in regulating diseases such as intestinal disorders, nephritis, and dermatitis. Further, through LASSO regression analysis and SVM-RFE algorithm analysis, we identified 9 key feature DEGs (CF-DEGs): ANGPTL7, TSHZ2, SDPR, CLCA4, PAMR1, MME, CXCL2, ADAMTS5, and KIT. Additionally, ROC curve analysis demonstrated that these CF-DEGs serve as a reliable diagnostic index. Finally, using the CIBERSORT algorithm, we analyzed the infiltration of immune cells and the associations between CF-DEGs and immune cell infiltration across all samples. Conclusions: Our findings provide new insights into the molecular functions and metabolic pathways involved in breast cancer, potentially aiding in the discovery of new diagnostic and immunotherapeutic biomarkers. [ABSTRACT FROM AUTHOR]