Members Of Breast Cancer Families Research Articles

Comprehensive analysis of the prognostic value of glutathione S-transferases Mu family members in breast cancer.

Breast cancer (BC) remains a significant public health concern globally, with a high number of reported cases and a substantial number of deaths every year. Accumulating reactive oxygen species (ROS) and oxidative stress are related to BC and the Glutathione S-transferases Mu (GSTM) family is one of the most important enzymatic detoxifiers associated with many cancers. In this study, UALCAN, Kaplan-Meier plotter, bc-GenExMiner, cBioPortal, STRING, Enrichr, and TIMER databases were employed to carry out a comprehensive bioinformatic analysis and provide new insight into the prognostic value of GSTMs in BC. GSTM2-5 genes in mRNA and protein levels were found to be expressed at lower levels in breast tumors compared to normal tissues, and reduction in mRNA levels is linked to shorter overall survival (OS) and relapse-free survival (RFS). The lower mRNA levels of GSTMs were strongly associated with the worse Scarff-Bloom-Richardson (SBR) grades (p < 0.0001). The mRNA levels of all five GSTMs were substantially higher in estrogen receptor (ER)-positive and progesterone receptor (PR)-positive compared to ER-negative and PR-negative BC patients. As well, when nodal status was compared, GSTM1, GSTM3, and GSTM5 were significantly higher in nodal-positive BC patients (p < .01). Furthermore, GSTM4 had the most gene alteration (4%) among other family members, and GSTM5 showed the strongest correlation with CD4+ T cells (Cor= .234, p = 2.22e-13). In conclusion, our results suggest that GSTM family members may be helpful as biomarkers for prognosis and as therapeutic targets in BC.

Comprehensive characterization of B7 family members in breast cancer: B7-H5 switch reverses breast cancer from “immuno-cold” into “immuno-hot” status

The members of the classic B7 family regulate the immune microenvironment of several malignant tumors. However, the potential relationship between the B7 family and the breast cancer (BrCa) tumor immune microenvironment has remained elusive. In the present study, we provide a comprehensive explanation of the expression, clinical significance, mutation, and immune cell infiltration of B7 family molecules in BrCa. First, we recruited 10 patients with BrCa surgery from the Wuxi Maternal and Child Health Hospital and performed single-cell RNA sequencing (scRNA-seq) analysis to investigate the distribution of B7 family members in multiple immune cell subsets. We focused on B7-2, B7-H3, and B7-H5 molecules of the B7 family and constructed tumor microarrays by self-recruiting patients to perform multiple immunohistochemical (mIHC) analyses and study tumor expression of B7-2, B7-H3, B7-H5 and CD8+ immune cell infiltration. B7-H5 displayed a strong correlation with CD8+ immune cell infiltration. In summary, B7-H5 provides a new perspective for the identification of immunothermal subtypes of BrCa and could function as a switch to reverse BrCa from an “immunologically cold” state to an “immunologically hot” state.Graphical abstract

MiR-770-5p-induced cellular switch to sensitize trastuzumab resistant breast cancer cells targeting HER2/EGFR/IGF1R bidirectional crosstalk.

Studies highlighted the bidirectional crosstalk between the HER family members in breast cancer as resistance mechanism to anti-HER agents. Cross-signaling between HER2/EGFR and ER/IGF1R could play role in the development of resistance to therapeutics hence stimulating cell growth. To overcome this resistance, combined therapies targeting both pathways simultaneously have been proposed as an effective strategy. The involvement of miRNAs in resistance of targeted therapies like trastuzumab was demonstrated in recent studies. Hence the regulation of miRNAs in resistance state could reverse the cell behaviour to drugs. Previously we found that overexpression of miR-770-5p downregulated AKT and ERK expression through HER2 signaling and potentiated the effect of trastuzumab. In this study we examined the impact of miR-770-5p on trastuzumab resistance. Cells were treated with tamoxifen or trastuzumab to examine their role in bidirectional crosstalk. The molecule mechanism of miR-770-5p on HER2/EGFR/IGF1R bidirectional crosstalk was explored by western blot. The expression of miR-770-5p in trastuzumab resistant cells was examined by q-PCR. To investigate the effect of miR-770-5p on cancer cell proliferation in trastuzumab resistance state, resistant cells were analyzed by iCELLigence real-time cell analyzer. miR-770-5p expression was significantly downregulated in trastuzumab-resistant BT-474 and SK-BR-3 cells. Overexpression of miR-770-5p sensitized the resistant cells to trastuzumab, as evidenced by reduced cell proliferation and increased cell viability. Additionally, in resistant cells, increased expression and activation of EGFR and IGF1R were observed. However, miR-770-5p overexpression resulted in decreased phosphorylation of AKT and ERK, indicating its suppressive role in EGFR/HER2 signaling. Furthermore, miR-770-5p downregulated the expression of IGF1R and mTOR, suggesting its involvement in regulating the escape signaling mediated by IGF1R in resistance. In conclusion, our findings demonstrate the critical role of miR-770-5p in regulating bidirectional crosstalk and overcoming trastuzumab resistance in breast cancer cells. These results highlight the potential of miR-770-5p as a therapeutic target to improve the efficacy of targeted therapies and address resistance mechanisms in breast cancer.

Abstract LB335: Steroid receptor cross-talk in breast cancer

Abstract Breast cancer is the most frequently diagnosed cancer in women worldwide. Oestrogen Receptor-α (ERα), is expressed in two thirds of human breast cancers, and the majority of patients are sensitive to endocrine therapy, i.e. anti-oestrogens or aromatase inhibitors that aim to block oestrogen signalling. In addition to ERα, the other members of the steroid receptor family (androgen, AR; progesterone, PR; glucocorticoid, GR; mineralocorticoid receptors, MR) also appear to play an important role in tumour development and recurrence, but the role of this signalling in cancer progression has not been fully characterised. Therefore, this study aims to address the role of the steroid receptor family members in breast cancer and to assess the effect of downstream signalling upon prognosis. Investigation of receptor signalling cross-talk using reporter, proliferation and migration assays, demonstrated that ERα and the other steroid receptors inhibit each other’s activity in endocrine responsive breast cancer cell lines, MCF7 and T47D. Furthermore, treatment with antioestrogen reversed the suppressive effects of ER𝛼;;; on the activity of the androgen, glucocorticoid progesterone receptors. To characterize receptor crosstalk on a global scale, RNA-seq and ChIP-seq datasets were analysed. Analysis of the ChIP-seq data demonstrated that the PR, GR and AR reprogramming of ERα results in the loss of ERα canonical binding sites and the gain of novel response elements/binding sites. Motif enrichment analysis of the novel ERα binding sites suggested that the altered binding in response to AR, GR and PR signalling, promotes the recruitment of ERα to androgen, glucocorticoid and progesterone response elements, respectively. Gene ontology analysis also revealed that this change in ERα binding sites is correlated with alterations in genes linked to cell proliferation and growth. Moreover, transcriptome studies showed that cotreatment of cells with estradiol and glucocorticoid or mineralocorticoid resulted in the upregulation of apoptotic signalling pathways. These findings may provide an explanation for the observed downregulation of GR and MR expression in ERα positive breast cancer. Patient datasets were used to investigate the prognostic significance of the steroid receptor target genes of interest, more specifically, those deregulated as a result of cross-talk. Considering overall survival and disease specific survival, univariate and multivariate Cox models with Lasso Regression were used to identify prognostic gene signatures using RNA_seq datasets. Kaplan-Meier (KM) and ROC analyses were applied to evaluate risk models. Established genetic markers associated with MR, AR, GR and PR was used to stratify BC patients into low and high risk groups. Patients survival was found to be positively correlated with these signatures, demonstrates that these gene sets have prognostic value. Further studies are required to validate these preliminary results to understand the role of steroid receptor crosstalk in breast cancer formation, progression, and survival. Citation Format: Aygun Azadova, Greg Brooke, Antonio Marco. Steroid receptor cross-talk in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB335.

NDRGs in Breast Cancer: A Review and In Silico Analysis.

The N-myc downstream regulated gene family (NDRGs) includes four members: NDRG1, NDRG2, NDRG3, and NDRG4. These members exhibit 53-65% amino acid identity. The role of NDRGs in tumor growth and metastasis appears to be tumor- and context-dependent. While many studies have reported that these family members have tumor suppressive roles, recent studies have demonstrated that NDRGs, particularly NDRG1 and NDRG2, function as oncogenes, promoting tumor growth and metastasis. Additionally, NDRGs are involved in regulating different signaling pathways and exhibit diverse cellular functions in breast cancers. In this review, we comprehensively outline the oncogenic and tumor suppressor roles of the NDRG family members in breast cancer, examining evidence from in vitro and in vivo breast cancer models as well as tumor tissues from breast cancer patients. We also present analyses of publicly available genomic and transcriptomic data from multiple independent cohorts of breast cancer patients.

Comprehensive Analysis of the Prognostic Marker and Immune Infiltrates of LDLR-Related Proteins Family Members in Breast Cancer

Comprehensive Analysis of the Prognostic Marker and Immune Infiltrates of LDLR-Related Proteins Family Members in Breast Cancer

Comprehensive Analysis of the Prognostic Marker and Immune Infiltrates of LDLR-Related Proteins Family Members in Breast Cancer.

Breast cancer (BC) is one of the most frequent tumors worldwide, accounting for 15% of all cancer-related deaths. A timely diagnosis of BC is essential for optimal treatment and increasing patients' survival rates. LRP family proteins are important components of cell-surface receptors involved in numerous biological activities. Expression of LRP is related to breast malignancy. In this study, we initially studied the expression of LRPs in BC tissues compared to normal tissues-the relation of LRP expression with relapse-free survival (RFS) and overall survival (OS). Then, we investigated the association of LRPs relation and immune infiltrating abundance. We analyzed the LDLR family expression and prognostic value in BC by mining UALCAN, TIMER, and Kaplan-Meier plotter databases. Subsequently, we explored the association of LDLR expression and immune infiltrating abundance via the TIMER database. Expression levels of LRP1/2/4/9/10 were found to be higher in the cases with positive estrogen receptors. There was a positive association between LRP1/6 expression and the infiltration of CD8+ T cells, CD4+ T Cell, Macrophage, Dendritic Cell, and Neutrophil. Our study recommends LDLR as a potential prognostic biomarker that can be promising to improve the survival of BC patients' survival. However, further investigations are needed to evaluate the studied LDLR members in more detail.

Comprehensive analysis of ACKR family members in breast cancer using prognostic values.

Breast cancer (BC) is by far the most prevalent malignancy found in the female population. Atypical chemokine receptors (ACKRs) are a subclass of G-protein-coupled receptors, which are characterized by disrupted ligand binding and a breakdown of signaling following ligand binding. The evolution and function of multiple ACKRs in BC have yet to be fully elucidated, although certain findings on this family have been reported in several studies in Homo sapiens and other species. The present study identified that the expression level of ACKRs was significantly lower in breast carcinoma (BRCA) tissues compared with normal breast tissues through searches of the Tumor Immune Estimation Resource, UALCAN and Gene Expression Profiling Interactive Analysis databases. Additionally, when comparing BRCA tissues with normal breast tissues, it was found that there was obvious hypomethylation in the promoters of ACKR1, ACKR3 and ACKR5, as well as a marked hypermethylation in the promoters of ACKR2 and ACKR6. In determining the prognosis of patients with BRCA, the expression levels of ACKR1, ACKR2, ACKR3, ACKR4 and ACKR6 were all found to be important factors. The values for distant metastasis-free survival (DMFS), overall survival (OS) and recurrence-free survival (RFS) were all found to be lower in patients with BRCA who had a low expression level of ACKR1. In addition, the RFS rates for patients with BRCA were lower when the expression of ACKR2 was low, and worse values for DMFS, OS and RFS were found to be highly correlated with higher expression levels of ACKR3. Moreover, the DMFS, OS, RFS and predictive power score values were worse in those patients with low ACKR4 expression, and the RFS values for patients with BRCA were also found to be lower when the expression level of ACKR6 was low. Additionally, dendritic cells, macrophages, neutrophils, T cells with CD4+ status, T cells with CD8+ status and B cells were all substantially linked with ACKR expression, as well as immune cell infiltration. Taken together, the findings of the present study may offer a theoretical foundation for the creation of novel targets and prognostic indicators for BRCA therapy.

Expression of Relt Family Members in Breast Cancer and Implications of a Novel Interaction with Filamin A

Journal of the American College of Surgeons 236(5):p S9, May 2023. | DOI: 10.1097/01.XCS.0000932308.96479.f1

Investigating the role of FADS family members in breast cancer based on bioinformatic analysis and experimental validation.

Breast cancer (BC) is the most common malignant tumor in women worldwide. Emerging evidence indicates the significance of fatty acid metabolism in BC. Fatty acid desaturase (FADS) is closely associated with cancer occurrence and development. Here, bioinformatic analysis and experimental validation were applied to investigate the potential functions of FADS in BC. Several public databases, including TCGA, GEO, HPA, Kaplan-Meier plotter, STRING, DAVID, cBioPortal, TIMER, TRRUST, and LinkedOmics were used to determine mRNA/protein expression levels, prognostic significance, functional enrichment, genetic alterations, association with tumor-infiltrating immune cells, and related transcription factors and kinases. BC tissues showed higher and lower mRNA expression of FADS2/6/8 and FADS3/4/5, respectively. FADS1/2/6 and FADS3/4/5 showed higher and lower protein expression levels, respectively, in BC tissues. Moreover, FADS1/7 up- and FADS3/8 down-regulation predicted poor overall and recurrence-free survival, while FADS2/5 up- and FADS4 down-regulation were associated with poor recurrence-free survival. Receiver operating characteristic curves revealed that FADS2/3/4/8 were indicative diagnostic markers. FADS family members showing differential expression levels were associated with various clinical subtypes, clinical stages, lymph node metastasis status, copy number variants, DNA methylation, and miRNA regulation in BC. The mRNA expression level of FADS1/2/3/4/5/7/8 was observed to be significantly negatively correlated with DNA methylation. FADS1/2 upregulation was significantly correlated with clinical stages. FADS1/4 expression was obviously lower in BC patients with higher lymph node metastasis than lower lymph node metastasis, while FADS7/8 expression was obviously higher in BC patients with higher lymph node metastasis than lower lymph node metastasis. FADS family members showed varying degrees of genetic alterations, and Gene Ontology and KEGG pathway enrichment analyses suggested their involvement in lipid metabolism. Their expression level was correlated with immune cell infiltration levels. FADS2 was chosen for further validation analyses. We found FADS2 to be significantly over-expressed in clinical BC tissue samples. The proliferation, migration, and invasion abilities of MDA-MB-231 and BT474 cells were significantly reduced after FADS2 knockdown. Furthermore, FADS2 may promote the occurrence and development of BC cells via regulating the epithelial-mesenchymal transition (EMT) pathway. Altogether, our results suggest that FADS1/2/3/4 can serve as potential therapeutic targets, prognostic indicators, and diagnostic markers in patients with BC.

Comprehensive Analysis of the Expression and Prognosis of chromobox Family Members in Breast Cancer

Background: Chromobox proteins are canonical components of the Polycomb group family and play pivotal roles in several cancers. However, little is known about the function, prognostic value and drug sensitivity of CBX family members in breast cancer.Methods: In this study we investigated the expression, prognosis value and drug sensitivity of CBX family in breast cancer using the ONCOMINE, GEPIA, Human Protein Atlas and Kaplan-Meier Plotter databases, etc. and preliminary verified the expression of CBX family in breast cancer cell lines by RT-qPCR.Results: We found that the expression levels of CBX1/2/3/4/8 members were elevated in breast cancer tissues compared to adjacent normal breast tissues, while the expression levels of CBX6/7 genes were reduced in breast cancer tissue. In vitro qRT-PCR validated the expression differences of CBX1/2/3/4/8 in breast cancer cell lines. Further analysis showed expression of CBX family members was remarkably correlated with cancer subgroups. As nodal metastasis status increased, the mRNA expression of CBX1/2/3/4/8 members tended to be higher, while CBX6/7 tended to be lower. The expression of CBX1/2/3 was higher in patients with TP53 mutation and CBX6/7 expression tended to be lower in patients with TP53 mutation groups. High transcription levels of CBX2/3 were significantly associated with shorter overall survival in breast cancer patients, while lower expression of CBX4/5/6/7 members was associated with unfavorable overall survival. Moreover, a high mutation rate of CBX gene members (43%) was observed in breast cancer patients, and genetic alterations in CBX genes was associated with poor prognosis.Conclusion: Taken together, our results indicated that CBX2/3/6/7/8 could be considered prognostic and therapeutic biomarkers of breast cancer and are worthy of further study.

Biomarker potential of the LEF1/TCF family members in breast cancer: Bioinformatic investigation on expression and clinical significance

Biomarker potential of the LEF1/TCF family members in breast cancer: Bioinformatic investigation on expression and clinical significance

An In Silico Analysis Identified Members of the Pleckstrin Homology-Like Domain, Family B (PHLDB family) as Potential Prognostic and Predictive Biomarkers of Treatment Response in Breast Cancer Patients.

Breast cancer is the leading cause of morbidity and mortality in women worldwide. This malignant neoplasm can be classified into four clinically relevant subtypes according to the expression of a number of biomarkers. However, these tumors show considerable intratumoral heterogeneity and multidrug resistance. Members of the pleckstrin homology-like domain, family B (PHLDB) play a critical role in the regulation of p53 and AKT signaling pathways, important for cancer and cellular metabolism. The present study was performed to evaluate the expression pattern of PHLDB family members in breast cancer and its potential prognostic and predictive value for therapeutic response using bioinformatics tools. This in silico analysis was performed using several online repositories, including UALCAN, GEPIA2, bc-GenExMiner, KM Plotter, PrognoScan and ROC Plotter. PHLDB family genes were found to be differentially expressed in tumor samples when compared to healthy breast tissue samples. Furthermore, epigenetic regulation may be one of the regulatory mechanisms for the expression of these markers. The PHLDB family of genes proved to be potential markers for predicting the development of lymph node metastasis (p<0.0001) and poor clinical outcome. All members of the PHLDB family were significantly correlated with hormone receptors. High levels of PHLDBs expression were associated with worse overall survival and recurrence-free survival in breast cancer patients. Finally, our data demonstrate that members of the PHLDB family can be promising markers in the stratification of patients who may or may not respond to different available therapies. Our cumulative results demonstrate that PHLDB family members may be promising biomarkers for predicting prognosis and therapeutic response in breast cancer patients.

Focal Adhesion Kinase (FAK)-Hippo/YAP transduction signaling mediates the stimulatory effects exerted by S100A8/A9-RAGE system in triple-negative breast cancer (TNBC)

BackgroundUnderstanding the intricate signaling network involved in triple-negative breast cancer (TNBC) represents a challenge for developing novel therapeutic approaches. Here, we aim to provide novel mechanistic insights on the function of the S100A8/A9-RAGE system in TNBC.MethodsTNM plot analyzer, Kaplan-Meier plotter, Meta-analysis, GEPIA2 and GOBO publicly available datasets were used to evaluate the clinical significance of S100A8/A9 and expression levels of S100A8/A9, RAGE and Filamin family members in breast cancer (BC) subtypes. METABRIC database and Cox proportional hazard model defined the clinical impact of high RAGE expression in BC patients. Multiple bioinformatics programs identified the main enriched pathways within high RAGE expression BC cohorts. By lentiviral system, TNBC cells were engineered to overexpress RAGE. Western blotting, immunofluorescence, nucleus/cytoplasm fractionation, qRT-PCR, gene silencing and luciferase experiments were performed to identify signal transduction mediators engaged by RAGE upon stimulation with S100A8/A9 in TNBC cells. Proliferation, colony formation and transwell migration assays were carried out to evaluate the growth and migratory capacity of TNBC cells. Statistical analysis was performed by ANOVA and independent t-tests.ResultsWe found a remarkable high expression of S100A8 and S100A9 in BC, particularly in HER2-positive and TNBC, with the latter associated to worst clinical outcomes. In addition, high RAGE expression correlated with a poor overall survival in BC. Next, we determined that the S100A8/A9-RAGE system triggers FAK activation by engaging a cytoskeleton mechanosensing complex in TNBC cells. Through bioinformatics analysis, we identified the Hippo pathway as the most enriched in BC patients expressing high RAGE levels. In accordance with these data, we demonstrated the involvement of S100A8/A9-RAGE-FAK signaling in the control of Hippo/YAP activities, and we established the crucial contribution of RAGE-FAK-YAP circuitry in the growth and migratory effects initiated by S100A8/A9 in TNBC cells.ConclusionsThe present study provides novel mechanistic insights on RAGE actions in TNBC. Moreover, our findings suggest that RAGE-FAK-YAP transduction pathway could be exploited as a druggable system halting the aggressive TNBC subtype.

Comprehensive analysis of the expression, prognostic significance, and function of FAM83 family members in breast cancer

BackgroundThe FAM83 family plays a key role in tumorigenesis and cancer progression. However, the role of the FAM83 family in the development of breast tumors is unclear to date. This report explores the expression, prognostic significance, and function of the FAM83 family members in breast cancer using public databases.MethodsUALCAN database was used to explore the expression of FAM83 family members in breast cancer. Furthermore, we validated the expression of FAM83 family members in twenty pairs of breast cancer and normal tissues by RT-PCR. Kaplan–Meier plotter database was used to explore the prognostic significance of FAM83 family members in breast cancer. GeneMANIA and DAVID databases were used for functional and pathway enrichment analysis of genes co-expressed with FAM83A, FAM83D, FAM83F, and FAM83G. MEXPRESS and UALCAN databases were used to analyze the level of DNA promoter methylation of FAM83A, FAM83D, FAM83F, and FAM83G in breast cancer. TIMER database was utilized to explore the relationships between immune cell infiltration and FAM83A, FAM83D, FAM83F, and FAM83G expression.ResultsAmong FAM83 family members, FAM83A, FAM83D, FAM83F, and FAM83G were higher expressed in breast cancer than in normal tissues. We also validated the significant high expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA in breast cancer than in normal samples. Their increased expression has an adverse prognostic effect on breast cancer patients. These genes co-expressed with FAM83A, FAM83D, FAM83F, and FAM83G might take part in cell proliferation, G2/M transition of the mitotic cell cycle, regulation of apoptosis process and other cancer-related biological processes. In addition, they were mainly enriched in the Hippo signaling pathway, Hedgehog signaling pathway, PI3K/AKT signaling pathway, and other cancer-related pathways. We also found that promoter DNA methylation might regulate the expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA in most CpG islands. At last, we found the expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA was significantly related to immune cell infiltration.ConclusionsFAM83A, FAM83D, FAM83F, and FAM83G were highly expressed in breast cancer tissues and had an adverse effect on the survival outcomes of breast cancer patients. Also, they were involved in breast cancer-related signal pathways. Therefore, they might serve as potential therapeutic targets for breast cancer clinical treatment.

Comprehensive Analysis of the Expression and Prognosis for RAD51 Family in Human Breast Cancer.

PurposeThe RAD51 family of genes, including RAD51 and the five RAD51-like paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3), are known to be crucially associated with DNA damage repair pathway. Increasing evidence indicated that RAD51 family members were implicated in breast cancer tumorigenesis. However, their biological roles and prognostic values in breast cancer have yet to be clarified.MethodsIn this study, by using the Oncomine and GEPIA databases, we explored the transcriptional levels of RAD51 family members in breast cancer. Besides, the associations between RAD51 family expression and clinical features were evaluated by using the UALCAN database and Kaplan–Meier (KM) Plotter. We also analyzed the mutations of the RAD51 family and differentially altered genes from the cBioPortal database.ResultsWe found that RAD51 mRNA was significantly elevated in breast cancer samples than in normal tissues, while XRCC2 mRNA was downregulated. Besides, a remarkable correlation was detected between the expression of RAD51/RAD51B/XRCC2 genes and the breast cancer stage. Survival analysis utilizing the KM Plotter indicated that high RAD51 and XRCC3 mRNA was associated with a poor prognosis. Conversely, RFS data suggested that high levels of RAD51B/RAD51C/RAD51D/XRCC2 were associated with a favorable prognosis. Moreover, a high genetic variation rate of RAD51C (7%) was detected in breast cancer patients.ConclusionConclusively, we implied that RAD51 and XRCC3 might be potential targets for precision therapy in breast cancer and the RAD51B/RAD51C/RAD51D/XRCC2 genes have significant values for breast cancer prognosis.

Mining the prognostic significance and immune infiltration of STAT family members in human breast cancer by bioinformatics analysis

Growing evidence proved that signal transducer and activators of transcription (STAT) proteins are cytoplasmic transcription factors known to play key roles in many cellular biological processes and may be prognostic predictors of some cancers. However, the role of each STAT family members in breast cancer (BRCA) is diverse and controversial. This study aimed to systematic mine the prognostic significance and immune infiltration of STAT family member in human BRCA. Based on The Cancer Genome Atlas (TCGA) database, we used the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA) and The Human Protein Atlas to analyze the expression of STAT family members in normal human breast and tumor tissues. The Kaplan-Meier Plotter, GEPIA and PrognoScan were utilized to assess the prognostic value of different STATs in BRCA. Then we used the cBioPortal, STRING, GeneMANIA and Metascape to make further mutation analysis, protein-protein interaction (PPI) analysis and subsequent functional enrichment analysis. Finally, the "ESTIMATE" and "ggcorrplot" package of R 17 software were used for immune infiltration analysis. STAT2 [P<0.01, hazard ratio (HR) =1.23, 95% confidence interval (CI): 1.07-1.42] and STAT3 (P=0.018, HR =0.69, 95% CI: 0.51-0.94) could be an independent risk factor for predicting overall survival (OS). STAT4 could be used as an independent predictor of distant metastasis-free survival in BRCA based on both GSE19615 (P=0.021, HR =0.21, 95% CI: 0.06-0.79) and GSE2034 (P=0.015, HR =0.57, 95% CI: 0.37-0.90) datasets. Meanwhile, STAT5A, STAT5B and STAT6 also have been shown to independently predict the prognosis of BRCA. Additionally, the functional mechanisms of STAT4 co-expressed genes were mainly focused on immune-related pathways and its expression was associated with immune checkpoint-associated genes and immunomodulators in BRCA. Our study mined the prognostic significance of STAT family members in BRCA and their correlation with immune infiltration. The results suggest that individual STATs, except STAT1, may act as a prognostic biomarker for BRCA and provide a reference for further potential immunotherapies.

Integrative Analysis of the Expression Levels and Prognostic Values for NEK Family Members in Breast Cancer.

Background: In the latest rankings, breast cancer ranks first in incidence and fifth in mortality among female malignancies worldwide. Early diagnosis and treatment can improve the prognosis and prolong the survival of breast cancer (BC) patients. The NIMA-related kinase (NEK), a group of serine/threonine kinase, is a large and conserved gene family that includes NEK1–NEK11. The NEK plays a pivotal role in the cell cycle and microtubule formation. However, an integrative analysis of the effect and prognosis value of NEK family members on BC patients is still lacking. Methods: In this study, the expression profiles of NEK family members in BC and its subgroups were analyzed using UALCAN, GEPIA2, and Human Protein Atlas datasets. The prognostic values of NEK family members in BC were evaluated using the Kaplan–Meier plotter. Co-expression profiles and genetic alterations of NEK family members were analyzed using the cBioPortal database. The function and pathway enrichment analysis of the NEK family were performed using the WebGestalt database. The correlation analysis of the NEK family and immune cell infiltration in BC was conducted using the TIMER 2.0 database. Results: In this study, we compared and analyzed the prognosis values of the NEKs. We found that NEK9 was highly expressed in normal breast tissues than BC, and NEK2, NEK6, and NEK11 were significantly highly expressed in BC than adjacent normal tissues. Interestingly, the expression levels of NEK2, NEK6, and NEK10 were not only remarkably correlated with the tumor stage but also with the molecular subtype. Through multilevel research, we found that high expression levels of NEK1, NEK3, NEK8, NEK9, NEK10, and NEK11 suggested a better prognosis value in BC, while high expression levels of NEK2 and NEK6 suggested a poor prognosis value in BC. Conclusion: Our studies show the prognosis values of the NEKs in BC. Thus, we suggest that NEKs may be regarded as novel biomarkers for predicting potential prognosis values and potential therapeutic targets of BC patients.

A comprehensive analysis of the diagnostic and prognostic value associated with the SLC7A family members in breast cancer.

The solute carrier (SLC) 7 family genes play central roles in cancer cell metabolism as glucose and glutamate transporters. However, their expression and prognostic value in breast cancer (BC) remains to be elucidated. Clinical data from BC patients were downloaded from The Cancer Genome Atlas (TCGA) and the Kaplan-Meier (KM) plotter database. The mechanisms underlying the association between SLC7A expression and overall survival (OS) were explored using Cox regression and log-rank tests. ESTIMATE gives a measure of the immune-cell infiltrates. Single-sample (ss) Gene Set Enrichment Analysis (GSEA) was conducted to quantify immune cell infiltration. High SLC7A5 expression was associated with a poorer survival time in BC patients according to the TCGA and KM plotter data. SLC7A4 was associated with good progression-free interval (PFI) and disease-specific survival (DSS) according to the TCGA data. Furthermore, SLC7A4 was correlated with good prognosis of OS, distant metastasis-free survival (DMFS), relapse-free survival (RFS), and post-progression survival (PPS) according to the KM plotter data. SLC7A3 expression was positively associated with OS, but was not strongly associated with PFI nor DSS in the TCGA data. However, SLC7A3 was positively correlated with DMFS and RFS in the KM database analysis. SLC7A had excellent diagnostic value in BC patients and was strongly correlated with tumor infiltration. T helper 2 (Th2) cells, CD56 bright natural killer (NK) cells, and NK cells were the most strongly correlated with the SLC7A family genes, suggesting that these genes play a crucial role in BC partly by modulating immune infiltration. SLC7A4 and SLC7A5 expression levels may be sensitive biomarkers for predicting BC outcomes. SLC7A3 may be a potential diagnostic and prognostic biomarker in BC, but further studies are warranted to verify these results.

Integrative Analysis of Prognostic Value and Immune Infiltration of Spindle and Kinetochore-associated Family Members in Breast Cancer

ABSTRACT Spindle and kinetochore associated (SKA) complex subunit, which maintains the stability of mitotic metaphase, with emerging research implying its effect as a carcinogenic regulator in cancer. However, its potential role in BC has not been fully elucidated. ONCOMINE, UALCAN, GEPIA, Kaplan-Meier Plotter, cBioPortal and TIMER databases were performed to analyze the expression, prognosis, mutation, immune infiltration and potential biological mechanisms of SKA1/2/3 in BC. Our results showed that SKA1/2/3 expression was upregulated in BC. Survival analysis reveals that SKA3 overexpression was associated with poor overall survival (OS), relapse-free survival (RFS), post-progression survival (PPS) and distant metastasis-free survival (DMFS). SKA1 overexpression was associated with poor OS, RFS and DMFS while SKA2 overexpression was only associated with RFS and DMFS. Notably, the results implied that SKA1 has a good prognostic value in HER2-positive BC. Besides, the genetic alterations of SKA were investigated and the altered group correlated with shorter progress-free survival (PFS) and disease-specific survival (DSS). GO and KEGG analysis showed that SKA1/2/3 were implicated in regulating cell cycle, p53 signaling pathway and DNA replication. The 10 Hub genes in the protein network were upregulated in BC and related to poorer prognosis. Additionally, SKA1/2/3 expression was negatively correlated with infiltration of various immune cells with antitumor effects, whereas positively correlated with the expression of immune checkpoints molecules. Further experiments revealed that SKA1/2/3 silencing markedly impeded the proliferation and migration of BC cells. Herein, our study firmly shows that SKA genes may serve as a promising therapeutic target for patients with BC.