Conduction and validation of a novel mitotic spindle assembly related signature in hepatocellular carcinoma: prognostic prediction, tumor immune microenvironment and drug susceptibility.

Introduction: We have developed a risk-scoring model using gene expression levels related to mitotic spindle assembly (MSA) to predict the prognosis of liver cancer. Methods and results: Initially, we identified 470 genes related to MSA from public databases. Subsequently, through analysis of sequencing data from liver cancer patient samples in online databases, we identified 7 genes suitable for constructing the risk-scoring model. We validated the predictive accuracy and clinical utility of the model. Through drug sensitivity analysis, we identified SAC3D1 as a gene sensitive to the most common anti-tumor drugs among these 7 genes. We propose SAC3D1 as a significant target for future clinical treatment. Furthermore, we conducted in vivo and in vitro experiments to validate the relevance of SAC3D1 to MSA and found its significant impact on the PI3K/Akt signaling pathway and spindle function. Conclusion: Our research introduces a novel risk-scoring model that accurately predicts liver cancer prognosis. Additionally, our findings suggest SAC3D1 as a promising therapeutic target for hepatocellular carcinoma, potentially revealing new mechanisms underlying liver cancer development.

Epsin 3 potentiates the NF­κB signaling pathway to regulate apoptosis in breast cancer.

Endocrine drug resistance is common in some patients with estrogen receptor (ER)­positive breast cancer, so it is necessary to identify potential therapeutic targets. The aim of the present study was to investigate the regulatory effect and mechanism of epsin 3 (EPN3) expression level changes on the proliferation and apoptosis of ER­positive breast cancer. Online GEPIA was used to analyze the expression level of EPN3 in breast cancer. The online Kaplan­Meier plotter tool was used to analyze the relationship between EPN3 expression and the prognosis of patients with breast cancer. Reverse transcription­quantitative PCR, immunohistochemistry and western blotting were performed to detect the mRNA and protein expression levels of EPN3 in breast cancer tissues and cells. A lentiviral infection system was used to knockdown the expression of EPN3 in breast cancer cell lines. Cell Counting Kit­8 and flow cytometry assays were conducted to detect the effect of EPN3 knockdown on breast cancer cell proliferation and apoptosis. Western blotting was used to detect the regulation of EPN3 expression on NF­κB, and immunofluorescence was performed to detect the effect of EPN3 expression on NF­κB nuclear translocation. The results demonstrated that the expression level of EPN3 in breast cancer tissues was higher compared with that in adjacent tissues (P<0.05). The expression level of EPN3 in the ER­positive breast cancer cell line, MCF7, was higher compared with that in the other cell lines (MCF10A, ZR75­1, MDA­MB­231, BT549 and SK­BR­3). After knocking down the expression of EPN3 in MCF7 cells, the proliferative ability of the cells was decreased, and the apoptosis rate was increased (P<0.05). After EPN3 knockdown in MCF7 cells, the phosphorylation of NF­κB was decreased (P<0.05), and the nuclear translocation signal was weakened. Thus, it was suggested that EPN3 promoted cell proliferation and inhibited cell apoptosis by regulating the NF­κB signaling pathway in ER­positive breast cancer.

Integrated multi-omics profiling of high-grade estrogen receptor-positive, HER2-negative breast cancer.

Estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+ HER2- ) breast cancer accounts for ~ 60-70% of all cases of invasive breast carcinoma. High-grade ER+ HER2- tumors respond poorly to endocrine therapy. In this study, we systematically analyzed clinical and multi-omics data to find potential strategies for personalized therapy of patients with high-grade ER+ HER2- disease. Six different cohorts were analyzed, for which multi-omics data were available. Grade III ER+ HER2- cases harbored higher proportions of large tumor size (> 5 cm), lymph node metastasis, chemotherapy use, and luminal B subtypes defined by PAM50, as compared with grade I/II tumors. DNA methylation (HM450) data and methylation-specific PCR indicated that the cg18629132 locus in the MKI67 promoter was hypermethylated in grade I/II cases and normal tissue, but hypomethylated in grade III cases or triple-negative breast cancer, resulting in higher expression of MKI67. Mutations in ESR1 and TP53 were detected in post-endocrine treatment metastatic samples at a higher rate than in treatment-naive tumors in grade III cases. We identified 42 and 20 focal copy number events in nonmetastatic and metastatic high-grade ER+ HER2- cases, respectively, with either MYC or MDM2 amplification representing an independent prognostic event in grade III cases. Transcriptional profiling within grade III tumors highlighted ER signaling downregulation and upregulation of immune-related pathways in non-luminal-like tumors defined by PAM50. Recursive partitioning analysis was employed to construct a decision tree of an endocrine-resistant subgroup (GATA3-negative and AGR-negative) of two genes that was validated by immunohistochemistry in a Chinese cohort. All together, these data suggest that grade III ER+ HER2- tumors have distinct clinical and molecular characteristics compared with low-grade tumors, particularly in cases with non-luminal-like biology. Due to the dismal prognosis in this group, clinical trials are warranted to test the efficacy of potential novel therapies.

The Potential Prognostic Role of Oligosaccharide-Binding Fold-Containing Protein 2A (OBFC2A) in Triple-Negative Breast Cancer.

BACKGROUND: Patients with triple-negative breast cancer (TNBC) have poor overall survival. The present study aimed to investigate the potential prognostics of TNBC by analyzing breast cancer proteomic and transcriptomic datasets. METHODS: Candidate proteins selected from CPTAC (the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium) were validated using datasets from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium). Kaplan-Meier analysis and ROC (receiver operating characteristic) curve analysis were performed to explore the prognosis of candidate genes. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis were performed on the suspected candidate genes. Single-cell RNA-seq (scRNA-seq) data from GSE118389 were used to analyze the cell clusters in which OBFC2A (Oligosaccharide-Binding Fold-Containing Protein 2A) was mainly distributed. TIMER (Tumor Immune Estimation Resource) was used to verify the correlation between OBFC2A expression and immune infiltration. Clone formation assays and wound healing assays were used to detect the role of OBFC2A expression on the proliferation, invasion, and migration of breast cancer cells. Flow cytometry was used to analyze the effects of silencing OBFC2A on breast cancer cell cycle and apoptosis. RESULTS: Six candidate proteins were found to be differentially expressed in non-TNBC and TNBC groups from CPTAC. However, only OBFC2A was identified as an independently poor prognostic gene marker in METABRIC (HR=3.658, 1.881-7.114). And OBFC2A was associated with immune functions in breast cancer. Biological functional experiments showed that OBFC2A might promote the proliferation and migration of breast cancer cells. The inhibition of OBFC2A expression blocked the cell cycle in G1 phase and inhibited the transformation from G1 phase to S phase. Finally, downregulation of OBFC2A also increased the total apoptosis rate of cells. CONCLUSION: On this basis, OBFC2A may be a potential prognostic biomarker for TNBC.

Long-term Survival Comparison of Repeated Breast-conserving Surgery Versus Mastectomy for Patients with DCIS with Ipsilateral Breast Tumor Recurrence: A Real-world Longitudinal Study.

BACKGROUND: Although patients diagnosed with ductal carcinoma in situ (DCIS) harbor excellent overall survival (OS) after breast-conserving therapy, the evidence regarding to surgical management for ipsilateral breast tumor recurrence (IBTR) is scarce. This study aimed to assess the prognosis of repeated breast-conserving surgery (BCS) versus mastectomy for IBTR in DCIS survivors. MATERIALS AND METHODS: Herein, 5344 DCIS cases with IBTR were identified during 702,748 person-years of follow-up, 3532 (66.09%) received mastectomy, and 1812 (33.91%) received repeated BCS. Cox regression and competing risk regression were employed to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for OS and breast cancer-specific survival (BCSS), which was respectively calculated within spontaneous and matched cohorts. RESULTS: After adjustment for confounders, no statistically significant survival difference was observed between the repeated BCS and mastectomy for patients with DCIS with IBTR. The stratified analyses further revealed that patients with DCIS with IBTR receiving repeated BCS combined with radiation therapy were associated with both superior OS (HR, 0.79; CI, 0.64-0.98; P = .04) and BCSS (HR, 0.54; CI, 0.33-0.90; P = .02) compared with counterparts undergoing mastectomy. Furthermore, patients with DCIS who were age older than 60 years at IBTR diagnosis benefit from repeated BCS with radiotherapy (HR, 0.44; CI, 0.24-0.84; P = .01) than mastectomy. CONCLUSION: We suggest that repeated BCS with radiation therapy deserves consideration when DCIS survivors suffered IBTR. The choice of surgical management should be tailored based on patients' age at IBTR diagnosis and size of recurrent disease.

Identification of autophagy-related long non-coding RNA prognostic signature for breast cancer.

Autophagy-related long non-coding RNAs (lncRNAs) disorders are related to the occurrence and development of breast cancer. The purpose of this study is to explore whether autophagy-related lncRNA can predict the prognosis of breast cancer patients. The autophagy-related lncRNAs prognostic signature was constructed by Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. We identified five autophagy-related lncRNAs (MAPT-AS1, LINC01871, AL122010.1, AC090912.1, AC061992.1) associated with prognostic value, and they were used to construct an autophagy-related lncRNA prognostic signature (ALPS) model. ALPS model offered an independent prognostic value (HR = 1.664, 1.381-2.006), where this risk score of the model was significantly related to the TNM stage, ER, PR and HER2 status in breast cancer patients. Nomogram could be utilized to predict survival for patients with breast cancer. Principal component analysis and Sankey Diagram results indicated that the distribution of five lncRNAs from the ALPS model tends to be low-risk. Gene set enrichment analysis showed that the high-risk group was enriched in autophagy and cancer-related pathways, and the low-risk group was enriched in regulatory immune-related pathways. These results indicated that the ALPS model composed of five autophagy-related lncRNAs could predict the prognosis of breast cancer patients.

Vitamin K intake and breast cancer incidence and death: results from a prospective cohort study.

BACKGROUND & AIMS: Vitamin K prevents growth and metastasis of certain cancers, but there is little evidence regarding the association between dietary vitamin K and breast cancer incidence and death. We sought to examine whether intakes of total vitamin K, phylloquinone (vitamin K1) and menaquinones (MKs) (vitamin K2) may influence risks of breast cancer incidence and death in the US population. METHODS: Herein, 2286 breast cancer cases and 207 breast cancer deaths were identified during 702,748 person-years of follow-up. Cox regression and competing risk regression were used to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (95% CIs) by dietary vitamin K intake quintile (Q) for risk of breast cancer incidence and mortality. RESULTS: After adjustment for confounders, the total MK intake was associated with an increased risk of breast cancer (HR Q5 vs Q1, 1.26; 95% CI, 1.05 to 1.52; Ptrend, 0.01) and death from breast cancer (HR Q5 vs Q1, 1.71; 95% CI, 0.97 to 3.01; Ptrend, 0.04). Non-linear positive dose-response associations with risks of breast cancer incidence and death were found for total MKs intake (Pnon-linearity<0.05). No statistically significant associations were observed between the intake of total vitamin K and phylloquinone and breast cancer. CONCLUSIONS: The present study suggests that total MK intake was associated with an altered risk of the occurrence and death of breast cancer in the general US population. If our findings are replicated in other epidemiological studies, reducing dietary intake of menaquinones may offer a novel strategy for breast cancer prevention.

Long-term anti-inflammatory diet in relation to improved breast cancer prognosis: a prospective cohort study.

Inflammation-modulating nutrients and inflammatory markers are established cancer risk factors, however, evidence regarding the association between post-diagnosis diet-associated inflammation and breast cancer survival is relatively sparse. We aimed to examine the association between post-diagnosis dietary inflammatory index (DII®) and risks of all-cause and breast cancer-specific mortality. A total of 1064 female breast cancer survivors in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) Trial prospective cohort, were included in this analysis if they had completed the diet history questionnaire (DHQ). Energy-adjusted DII (E-DIITM) scores were calculated based on food and supplement intake. Cox regression and competing risk models were used to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (95% CIs) by E-DII tertile (T) for all-cause and breast cancer-specific mortality. With median follow-up of 14.6 years, there were 296 (27.8%) deaths from all causes and 100 (9.4%) breast cancer-specific death. The E-DII was associated with all-cause mortality (HR T3 vs T1, 1.34; 95% CI, 1.01-1.81; P trend, 0.049, Table 2) and breast cancer mortality (HR T3 vs T1, 1.47; 95% CI, 0.89-2.43; P trend, 0.13; multivariable-adjusted HR for 1-unit increment: 1.10; 95% CI: 1.00-1.22). Non-linear positive dose-response associations with mortality from all causes were identified for E-DII scores (P non-linearity < 0.05). The post-diagnosis E-DII was statistically significantly associated with mortality risk among breast cancer survivors. Long-term anti-inflammatory diet might be a means of improving survival of breast cancer survivors.