CCNE1 amplification is associated with poor prognosis in patients with triple negative breast cancer.
Zhao Zi-Ming,Yost Susan E,Hutchinson Katherine E,Li Sierra Min,Yuan Yate-Ching,Noorbakhsh Javad,Liu Zheng,Warden Charles,Johnson Radia M,Wu Xiwei,Chuang Jeffrey H,Yuan Yuan
BACKGROUND:Triple negative breast cancer (TNBC) is aggressive with limited treatment options upon recurrence. Molecular discordance between primary and metastatic TNBC has been observed, but the degree of biological heterogeneity has not been fully explored. Furthermore, genomic evolution through treatment is poorly understood. In this study, we aim to characterize the genomic changes between paired primary and metastatic TNBCs through transcriptomic and genomic profiling, and to identify genomic alterations which may contribute to chemotherapy resistance. METHODS:Genomic alterations and mRNA expression of 10 paired primary and metastatic TNBCs were determined through targeted sequencing, microarray analysis, and RNA sequencing. Commonly mutated genes, as well as differentially expressed and co-expressed genes were identified. We further explored the clinical relevance of differentially expressed genes between primary and metastatic tumors to patient survival using large public datasets. RESULTS:Through gene expression profiling, we observed a shift in TNBC subtype classifications between primary and metastatic TNBCs. A panel of eight cancer driver genes (CCNE1, TPX2, ELF3, FANCL, JAK2, GSK3B, CEP76, and SYK) were differentially expressed in recurrent TNBCs, and were also overexpressed in TCGA and METABRIC. CCNE1 and TPX2 were co-overexpressed in TNBCs. DNA mutation profiling showed that multiple mutations occurred in genes comprising a number of potentially targetable pathways including PI3K/AKT/mTOR, RAS/MAPK, cell cycle, and growth factor receptor signaling, reaffirming the wide heterogeneity of mechanisms driving TNBC. CCNE1 amplification was associated with poor overall survival in patients with metastatic TNBC. CONCLUSIONS:CCNE1 amplification may confer resistance to chemotherapy and is associated with poor overall survival in TNBC.
Revealing clonality and subclonality of driver genes for clinical survival benefits in breast cancer.
Lan Yujia,Zhao Erjie,Luo Shangyi,Xiao Yun,Li Xia,Cheng Shujun
Breast cancer research and treatment
PURPOSE:Genomic studies have revealed that genomic aberrations play important roles in the progression of this disease. The aim of this study was to evaluate the associations between clinical survival outcomes of the clonality and subclonality status of driver genes in breast cancer. METHODS:We performed an integrated analysis to infer the clonal status of 55 driver genes in breast cancer data from TCGA. We used the chi-squared test to assess the relations between clonality of driver gene mutations and clinicopathological factors. The Kaplan-Meier method was performed for the visualization and the differences between survival curves were calculated by log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to adjust for clinicopathological factors. RESULTS:We identified a high proportion of clonal mutations in these driver genes. Among them, there were 17 genes showing significant associations between their clonality and multiple clinicopathologic factors. Performing survival analysis on BRCA patients with clonal or subclonal driver gene mutations, we found that clonal ERBB2, FOXA1, and KMT2C mutations and subclonal GATA3 and RB1 mutations predicted shorter overall survival compared with those with wild type. Furthermore, clonal ERBB2 and FOXA1 mutations and subclonal GATA3 and RB1 mutations independently predicted for shorter overall survival after adjusting for clinicopathological factors. By longitudinal analysis, the clonality of ERBB2, FOXA1, GATA3, and RB1 significantly predicted patients' outcome within some specific BRCA tumor stages and histological subtypes. CONCLUSIONS:In summary, these clonal or subclonal mutations of driver genes have implications for diagnosis, prognosis, and treatment with BRCA patients.
Integrated omics-based pathway analyses uncover CYP epoxygenase-associated networks as theranostic targets for metastatic triple negative breast cancer.
Apaya Maria Karmella,Shiau Jeng-Yuan,Liao Guo-Shiou,Liang Yu-Jen,Chen Chia-Wei,Yang Hsin-Chou,Chu Chi-Hong,Yu Jyh-Cherng,Shyur Lie-Fen
Journal of experimental & clinical cancer research : CR
BACKGROUND:Current prognostic tools and targeted therapeutic approaches have limited value for metastatic triple negative breast cancer (TNBC). Building upon current knowledge, we hypothesized that epoxyeicosatrienoic acids (EETs) and related CYP450 epoxygenases may have differential roles in breast cancer signaling, and better understanding of which may uncover potential directions for molecular stratification and personalized therapy for TNBC patients. METHODS:We analyzed the oxylipin metabolome of paired tumors and adjacent normal mammary tissues from patients with pathologically confirmed breast cancer (N = 62). We used multivariate statistical analysis to identify important metabolite contributors and to determine the predictive power of tumor tissue metabolite clustering. In vitro functional assays using a panel of breast cancer cell lines were carried out to further confirm the crucial roles of endogenous and exogenous EETs in the metastasis transformation of TNBC cells. Deregulation of associated downstream signaling networks associated with EETs/CYPs was established using transcriptomics datasets from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Comparative TNBC proteomics using the same tissue specimens subjected to oxylipin metabolomics analysis was used as validation set. RESULTS:Metabolite-by-metabolite comparison, tumor immunoreactivity, and gene expression analyses showed that CYP epoxygenases and arachidonic acid-epoxygenation products, EET metabolites, are strongly associated with TNBC metastasis. Notably, all the 4 EET isomers (5,6-, 8,9-, 11,12-, and 14,15-EET) was observed to profoundly drive the metastasis transformation of mesenchymal-like TNBC cells among the TNBC (basal- and mesenchymal-like), HER2-overexpressing and luminal breast cancer cell lines examined. Our pathway analysis revealed that, in hormone-positive breast cancer subtype, CYP epoxygenase overexpression is more related to immune cell-associated signaling, while EET-mediated Myc, Ras, MAPK, EGFR, HIF-1α, and NOD1/2 signaling are the molecular vulnerabilities of metastatic CYP epoxygenase-overexpressing TNBC tumors. CONCLUSIONS:This study suggests that categorizing breast tumors according to their EET metabolite ratio classifiers and CYP epoxygenase profiles may be useful for prognostic and therapeutic assessment. Modulation of CYP epoxygenase and EET-mediated signaling networks may offer an effective approach for personalized treatment of breast cancer, and may be an effective intervention option for metastatic TNBC patients.
Toward the precision breast cancer survival prediction utilizing combined whole genome-wide expression and somatic mutation analysis.
Zhang Yifan,Yang William,Li Dan,Yang Jack Y,Guan Renchu,Yang Mary Qu
BMC medical genomics
BACKGROUND:Breast cancer is the most common type of invasive cancer in woman. It accounts for approximately 18% of all cancer deaths worldwide. It is well known that somatic mutation plays an essential role in cancer development. Hence, we propose that a prognostic prediction model that integrates somatic mutations with gene expression can improve survival prediction for cancer patients and also be able to reveal the genetic mutations associated with survival. METHOD:Differential expression analysis was used to identify breast cancer related genes. Genetic algorithm (GA) and univariate Cox regression analysis were applied to filter out survival related genes. DAVID was used for enrichment analysis on somatic mutated gene set. The performance of survival predictors were assessed by Cox regression model and concordance index(C-index). RESULTS:We investigated the genome-wide gene expression profile and somatic mutations of 1091 breast invasive carcinoma cases from The Cancer Genome Atlas (TCGA). We identified 118 genes with high hazard ratios as breast cancer survival risk gene candidates (log rank p < 0.0001 and c-index = 0.636). Multiple breast cancer survival related genes were found in this gene set, including FOXR2, FOXD1, MTNR1B and SDC1. Further genetic algorithm (GA) revealed an optimal gene set consisted of 88 genes with higher c-index (log rank p < 0.0001 and c-index = 0.656). We validated this gene set on an independent breast cancer data set and achieved a similar performance (log rank p < 0.0001 and c-index = 0.614). Moreover, we revealed 25 functional annotations, 15 gene ontology terms and 14 pathways that were significantly enriched in the genes that showed distinct mutation patterns in the different survival risk groups. These functional gene sets were used as new features for the survival prediction model. In particular, our results suggested that the Fanconi anemia pathway had an important role in breast cancer prognosis. CONCLUSIONS:Our study indicated that the expression levels of the gene signatures remain the effective indicators for breast cancer survival prediction. Combining the gene expression information with other types of features derived from somatic mutations can further improve the performance of survival prediction. The pathways that were associated with survival risk suggested by our study can be further investigated for improving cancer patient survival.
Clinical implications of a novel prognostic factor AIFM3 in breast cancer patients.
Zheng Ang,Zhang Lin,Song Xinyue,Wang Yuying,Wei Minjie,Jin Feng
BACKGROUND:In a time of increasing concerns over personalized and precision treatment in breast cancer (BC), filtering prognostic factors attracts more attention. Apoptosis-Inducing Factor Mitochondrion-associated 3 (AIFM3) is widely expressed in various tissues and aberrantly expressed in several cancers. However, clinical implication of AIFM3 has not been reported in BC. The aim of the study is to investigate the crystal structure, clinical and prognostic implications of AIFM3 in BC. METHODS:AIFM3 expression in 151 BC samples were assessed by immunohistochemistry (IHC). The Cancer Genome Atlas (TCGA) and Kaplan-Meier survival analysis were used to demonstrate expression and survival of AIFM3 signature. Gene Set Enrichment Analysis (GSEA) was performed to investigate the mechanisms related to AIFM3 expression in BC. RESULTS:AIFM3 was significantly more expressed in breast cancer tissues than in normal tissues. AIFM3 expression had a significant association with tumor size, lymph node metastasis, TNM stage and molecular typing. Higher AIFM3 expression was related to a shorter overall survival (OS) and disease-free survival (DFS). Lymph node metastasis and TNM stage were independent factors of AIFM3 expression. The study presented the crystal structure of AIFM3 successfully and predicted several binding sites when AIFM3 bonded to PTPN12 by Molecular Operating Environment software (MOE). CONCLUSIONS:AIFM3 might be a potential biomarker for predicting prognosis in BC, adding to growing evidence that AIFM3 might interact with PTPN12.
Clinical Value of miR-101-3p and Biological Analysis of its Prospective Targets in Breast Cancer: A Study Based on The Cancer Genome Atlas (TCGA) and Bioinformatics.
Li Chun-Yao,Xiong Dan-Dan,Huang Chun-Qin,He Rong-Quan,Liang Hai-Wei,Pan Deng-Hua,Wang Han-Lin,Wang Yi-Wen,Zhu Hua-Wei,Chen Gang
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND MiR-101-3p can promote apoptosis and inhibit proliferation, invasion, and metastasis in breast cancer (BC) cells. However, its mechanisms in BC are not fully understood. Therefore, a comprehensive analysis of the target genes, pathways, and networks of miR-101-3p in BC is necessary. MATERIAL AND METHODS The miR-101 profiles for 781 patients with BC from The Cancer Genome Atlas (TCGA) were analyzed. Gene expression profiling of GSE31397 with miR-101-3p transfected MCF-7 cells and scramble control cells was downloaded from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were identified. The potential genes targeted by miR-101-3p were also predicted. Gene Ontology (GO) and pathway and network analyses were constructed for the DEGs and predicted genes. RESULTS In the TCGA data, a low level of miR-101-2 expression might represent a diagnostic (AUC: 0.63) marker, and the miR-101-1 was a prognostic (HR=1.79) marker. MiR-101-1 was linked to the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), and miR-101-2 was associated with the tumor (T), lymph node (N), and metastasis (M) stages of BC. Moreover, 427 genes were selected from the 921 DEGs in GEO and the 7924 potential target genes from the prediction databases. These genes were related to transcription, metabolism, biosynthesis, and proliferation. The results were also significantly enriched in the VEGF, mTOR, focal adhesion, Wnt, and chemokine signaling pathways. CONCLUSIONS MiR-101-1 and miR-101-2 may be prospective biomarkers for the prognosis and diagnosis of BC, respectively, and are associated with diverse clinical parameters. The target genes of miR-101-3p regulate the development and progression of BC. These results provide insight into the pathogenic mechanism and potential therapies for BC.
Immune microenvironment of triple-negative breast cancer in African-American and Caucasian women.
O'Meara Tess,Safonov Anton,Casadevall David,Qing Tao,Silber Andrea,Killelea Brigid,Hatzis Christos,Pusztai Lajos
Breast cancer research and treatment
PURPOSE:African-American (AA) patients with triple-negative breast cancer (TNBC) are less likely to achieve pathologic complete response from neoadjuvant chemotherapy and have poorer prognosis than Caucasian patients with TNBC, suggesting potential biological differences by race. Immune infiltration is the most consistent predictive marker for chemotherapy response and improved prognosis in TNBC. In this study, we test the hypothesis that the immune microenvironment differs between AA and Caucasian patients. METHODS:RNA-seq expression data were obtained from The Cancer Genome Atlas (TCGA) database for 162 AA and 697 Caucasian breast cancers. Estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-positive, and TNBC subtypes were included in the analyses. Tumor infiltrating lymphocyte (TIL) counts, immunomodulatory scores, and molecular subtypes were obtained from prior publications for a subset of the TNBC cases. Differences in immune cell distributions and immune functions, measured through gene expression and TIL counts, as well as neoantigen, somatic mutation, amplification, and deletion loads, were compared by race and tumor subtype. RESULTS:Immune metagene analysis demonstrated marginal immune attenuation in AA TNBC relative to Caucasian TNBC that did not reach statistical significance. The distributions of immune cell populations, lymphocyte infiltration, molecular subtypes, and genomic aberrations between AA and Caucasian subtypes were also not significantly different. The MHC1 metagene demonstrated increased expression in AA ER-positive cancers relative to Caucasian ER-positive cancers. CONCLUSIONS:This study suggests that the immunological differences between AA and Caucasian breast cancers represented by TCGA data are subtle, if they exist at all. We observed no consistent racial differences in immune gene expression or TIL counts in TNBC by race. However, this study cannot rule out small differences in immune cell subtype distribution and activity status that may not be apparent in bulk RNA analysis.
Prognostic value of DKK2 from the Dickkopf family in human breast cancer.
Shao You-Cheng,Nie Xiao-Cui,Song Guo-Qing,Wei Yan,Xia Pu,Xu Xiao-Yan
International journal of oncology
Breast cancer is one of the most frequently diagnosed types of cancer with a high mortality and malignancy rate in women worldwide. The Dickkopf (DKK) protein family, as a canonical Wnt/β-catenin pathway antagonist, has been implicated in both physiological and pathological processes. This study aimed to comprehensively characterize the prognostic value and elucidate the mechanisms of DKKs in breast cancer and its subtypes. Firstly, DKK mRNA expression and corresponding outcome were analyzed by means of the Gene Expression-Based Outcome for Breast Cancer Online (GOBO) platform based on PAM50 intrinsic breast cancer subtypes. Subsequently, we extracted breast cancer datasets from the Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) to validate the expression profile and prognostic values from the GOBO platform. Moreover, a protein-protein network was created and functional enrichment was conducted to explore the underlying mechanisms of action of the DKKs. In addition, we uncovered the genetic and epigenetic alterations of DKK2 in breast cancer. The main finding of this study was the differential roles of DKKs in the PAM50 subtypes of breast cancer analyzed. The overall trend was that a high level of DKK2 was associated with a good survival in breast cancer, although it played an opposite role in the Normal-like subtype. We also found that DKK2 carried out its functions through multiple signaling pathways, not limited to the Wnt/β-catenin cascade in breast cancer. Finally, we used our own data to validate the bioinformatics analysis data for DKK2 by RT-qPCR. Taken together, our findings suggest that DKK2 may be a potential prognostic biomarker for the Normal-like subtype of breast cancer. However, the prognostic role of DKKs in the subtypes of breast cancer still requires validation by larger sample studies in the future.
Identification of MicroRNAs as Breast Cancer Prognosis Markers through the Cancer Genome Atlas.
Chang Jeremy T-H,Wang Fan,Chapin William,Huang R Stephanie
Breast cancer is the second-most common cancer and second-leading cause of cancer mortality in American women. The dysregulation of microRNAs (miRNAs) plays a key role in almost all cancers, including breast cancer. We comprehensively analyzed miRNA expression, global gene expression, and patient survival from the Cancer Genomes Atlas (TCGA) to identify clinically relevant miRNAs and their potential gene targets in breast tumors. In our analysis, we found that increased expression of 12 mature miRNAs-hsa-miR-320a, hsa-miR-361-5p, hsa-miR-103a-3p, hsa-miR-21-5p, hsa-miR-374b-5p, hsa-miR-140-3p, hsa-miR-25-3p, hsa-miR-651-5p, hsa-miR-200c-3p, hsa-miR-30a-5p, hsa-miR-30c-5p, and hsa-let-7i-5p -each predicted improved breast cancer survival. Of the 12 miRNAs, miR-320a, miR-361-5p, miR-21-5p, miR-103a-3p were selected for further analysis. By correlating global gene expression with miRNA expression and then employing miRNA target prediction analysis, we suggest that the four miRNAs may exert protective phenotypes by targeting breast oncogenes that contribute to patient survival. We propose that miR-320a targets the survival-associated genes RAD51, RRP1B, and TDG; miR-361-5p targets ARCN1; and miR-21-5p targets MSH2, RMND5A, STAG2, and UBE2D3. The results of our stringent bioinformatics approach for identifying clinically relevant miRNAs and their targets indicate that miR-320a, miR-361-5p, and miR-21-5p may contribute to breast cancer survival.
Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity.
Qin Tao,Li Bai,Feng Xiaoyue,Fan Shujun,Liu Lei,Liu Dandan,Mao Jun,Lu Ying,Yang Jinfeng,Yu Xiaotang,Zhang Qingqing,Zhang Jun,Song Bo,Li Man,Li Lianhong
Journal of experimental & clinical cancer research : CR
BACKGROUND:Recent studies have indicated that deubiquitinating enzymes (DUBs) are related to the stem-cell pathway network and chemo-resistance in cancer. Ubiquitin-specific peptidase 37 (USP37), a novel DUB, was identified to be a potential factor associated with tumor progression. However, the biological functions of USP37 in breast cancer remain unclear. METHODS:The distribution of USP37 expression in breast cancer and the correlation between USP37 expression and the overall survival rate were detected by The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was utilized to evaluate potential mechanism of USP37 in breast cancer. The USP37 expression in breast cancer tissues and breast cancer cell lines were detected by immunohistochemistry and western blotting. Sorting of breast cancer stem cells (BCSCs) were by using MACS assay. In vitro and in vivo assays were performed to examine the biological functions of USP37 in breast cancer cells. MG132, CHX chase, immunofluorescence staining and co-immunoprecipitation assays were used to test the interaction between USP37 and Gli-1. RESULTS:Bioinformatics analysis demonstrated that USP37 gene was elevated in breast cancer tissues and its overexpression was strongly correlated with the increased mortality rate. GSEA analysis showed that USP37 expression was positively associated with cell growth and metastasis while negatively related to cell apoptosis in the TCGA breast cancer samples. USP37 expression was elevated in breast cancer tissues and breast cancer cell lines. Moreover, we also detected that USP37 was overexpressed in BCSCs. USP37 regulated the ability of cell invasion, epithelial-mesenchymal transition (EMT), stemness and cisplatin sensitivity in breast cancer cell lines. Additionally, USP37 knockdown inhibited tumorigenicity and increased anticancer effect of cisplatin in vivo. Knockdown of USP37 significantly decreased hedgehog (Hh) pathway components Smo and Gli-1. Gli-1 was stabilized by USP37 and they interacted with each other. Further studies indicated that USP37 knockdown could inhibit the stemness, cell invasion and EMT in breast cancer via downregulation of Hh pathway. CONCLUSIONS:These findings reveal that USP37 is highly expressed in BCSCs and is correlated with poor prognosis in breast cancer patients. USP37 can regulate the stemness, cell invasion and EMT via Hh pathway, and decreased USP37 confers sensitivity to cisplatin in breast cancer cells. USP37 is required for the regulation of breast cancer progression, as well as a critical target for clinical treatment of breast cancer.
An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes.
Győrffy Balázs,Pongor Lőrinc,Bottai Giulia,Li Xiaotong,Budczies Jan,Szabó András,Hatzis Christos,Pusztai Lajos,Santarpia Libero
British journal of cancer
BACKGROUND:Sequence variations in coding and non-coding regions of the genome can affect gene expression and signalling pathways, which in turn may influence disease outcome. METHODS:In this study, we integrated somatic mutations, gene expression and clinical data from 930 breast cancer patients included in the TCGA database. Genes associated with single mutations in molecular breast cancer subtypes were identified by the Mann-Whitney U-test and their prognostic value was evaluated by Kaplan-Meier and Cox regression analyses. Results were confirmed using gene expression profiles from the Metabric data set (n = 1988) and whole-genome sequencing data from the TCGA cohort (n = 117). RESULTS:The overall mutation rate in coding and non-coding regions were significantly higher in ER-negative/HER2-negative tumours (P = 2.8E-03 and P = 2.4E-07, respectively). Recurrent sequence variations were identified in non-coding regulatory regions of several cancer-associated genes, including NBPF1, PIK3CA and TP53. After multivariate regression analysis, gene signatures associated with three coding mutations (CDH1, MAP3K1 and TP53) and two non-coding variants (CRTC3 and STAG2) in cancer-related genes predicted prognosis in ER-positive/HER2-negative tumours. CONCLUSIONS:These findings demonstrate that sequence alterations influence gene expression and oncogenic pathways, possibly affecting the outcome of breast cancer patients. Our data provide potential opportunities to identify non-coding variations with functional and clinical relevance in breast cancer.
The Clinicopathological Significance and Correlative Signaling Pathways of an Autophagy-Related Gene, Ambra1, in Breast Cancer: a Study of 25 Microarray RNA-Seq Datasets and in-House Gene Silencing.
He Rong-Quan,Xiong Dan-Dan,Ma Jie,Hu Xiao-Hua,Chen Gang,Sun Wei-Liang
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
BACKGROUND/AIMS:The activating molecule in Beclin1-regulated autophagy (Ambra1) has been observed to be over-expressed in several cancers, but the clinical contribution of Ambra1 in breast cancer (BC) remains unknown. Hence, in this study, we conducted a comprehensive investigation into the expression, biological role, and underlying functional mechanism of Ambra1 in BC. METHODS:Microarray and RNA-seq datasets providing Ambra1 expression data were obtained from Gene Expression Omnibus (GEO), ArrayExpress, Oncomine, and The Cancer Genome Atlas (TCGA). Both standard mean deviation (SMD) and summary receiver operating characteristic methods were employed to assess Ambra1 expression in BC. We then silenced Ambra1 in MDA-MB-231 cells and performed in vitro experiments to explore the biological effects of Ambra1 on BC cells. Furthermore, differentially expressed genes (DEGs) after Ambra1 knock-down were profiled with a microarray and overlapped with the genes correlated with Ambra1 from Multi Experiment Matrix (MEM) and genes similar to Ambra1 from Gene Expression Profiling Interactive Analysis. These overlapping genes were collected for further bioinformatics analyses to investigate the underlying molecular mechanism of Ambra1 in BC. RESULTS:A total of 25 microarray and RNA-seq datasets involving 2460 breast cancer samples were included. The pooled results demonstrated that Ambra1 was markedly up-regulated in BC tissues (SMD=0.39, 95% CI=0.15-0.63; P=0.002), and the Ambra1 level was also significantly related to the progression of BC, especially metastasis status (P=0.004). In vitro experiments suggested that the proliferation of MDA-MB-231 cells transfected with Ambra1 short hairpin RNA (sh-RNA 2450) showed a decreasing trend at 48 h compared with the control (CK) group. However, apoptosis was similar in cells transfected with Ambra1 sh-RNAs and in the CK cells. Furthermore, we performed a microarray-based comparison of genes after Ambra1 knock-down. The 828 DEGs from microarray analysis were intersected with 4266 Ambra1 co-expressed genes from MEM. Eventually, the overlapped 183 genes were found to be enriched in several well-known cancer-related pathways, including the MAPK signaling pathway, chronic myeloid leukemia pathway, and VEGF signaling pathway. CONCLUSION:These results indicate that the level of Ambra1 up-regulation is clearly related to tumorigenesis and progression of BC, probably via influencing several vital pathways. However, this hypothesis needs to be validated with more in-depth experiments in the future.
A novel long non-coding RNA FGF14-AS2 is correlated with progression and prognosis in breast cancer.
Yang Fan,Liu Ye-Huan,Dong Si-Yang,Ma Rui-Ming,Bhandari Adheesh,Zhang Xiao-Hua,Wang Ou-Chen
Biochemical and biophysical research communications
Breast cancer is diverse in their natural history and in their responsiveness to treatments. It is urgent to generate candidate biomarkers for the stratification of patients and personalization of therapy to avoid overtreatment or inadequate treatment. Long noncoding RNAs (lncRNAs) have been found to be pervasively transcribed in the genome and played critical roles in cancer progression. A lot of lncRNAs have been reported as potential prognostic biomarkers and therapeutic targets in multiple cancers. In this study, we demonstrated that FGF14 antisense RNA 2 (FGF14-AS2), a novel long non-coding RNA, was significantly down-regulated in breast cancer tissue compared with adjacent normal tissue both in validated cohort and TCGA cohort. Reduced expression of FGF14-AS2 was correlated with larger tumor size, more lymph node metastasis and advanced clinical stage in both cohorts. Kaplan-Meier analysis indicated that patients with lower FGF14-AS2 expression had a worse overall survival. Moreover, multivariate analysis revealed that decreased expression of FGF14-AS2 was an independent predictor of overall survival. Together, these results suggested that FGF14-AS2 involved in the progress of breast cancer and might act as a tumor suppressor gene. To the best of our knowledge, it was firstly reported that FGF14-AS2 was involved in cancer. This study provided a potential new marker and a target for gene therapy in breast cancer treatment.
Roadmap of DNA methylation in breast cancer identifies novel prognostic biomarkers.
de Almeida Bernardo P,Apolónio Joana Dias,Binnie Alexandra,Castelo-Branco Pedro
BACKGROUND:Breast cancer is a highly heterogeneous disease resulting in diverse clinical behaviours and therapeutic responses. DNA methylation is a major epigenetic alteration that is commonly perturbed in cancers. The aim of this study is to characterize the relationship between DNA methylation and aberrant gene expression in breast cancer. METHODS:We analysed DNA methylation and gene expression profiles from breast cancer tissue and matched normal tissue in The Cancer Genome Atlas (TCGA). Genome-wide differential methylation analysis and methylation-gene expression correlation was performed. Gene expression changes were subsequently validated in the METABRIC dataset. The Oncoscore tool was used to identify genes that had previously been associated with cancer in the literature. A subset of genes that had not previously been studied in cancer was chosen for further analysis. RESULTS:We identified 368 CpGs that were differentially methylated between tumor and normal breast tissue (∆β > 0.4). Hypermethylated CpGs were overrepresented in tumor tissue and were found predominantly (56%) in upstream promoter regions. Conversely, hypomethylated CpG sites were found primarily in the gene body (66%). Expression analysis revealed that 209 of the differentially-methylated CpGs were located in 169 genes that were differently expressed between normal and breast tumor tissue. Methylation-expression correlations were predominantly negative (70%) for promoter CpG sites and positive (74%) for gene body CpG sites. Among these differentially-methylated and differentially-expressed genes, we identified 7 that had not previously been studied in any form of cancer. Three of these, TDRD10, PRAC2 and TMEM132C, contained CpG sites that showed diagnostic and prognostic value in breast cancer, particularly in estrogen-receptor (ER)-positive samples. A pan-cancer analysis confirmed differential expression of these genes together with diagnostic and prognostic value of their respective CpG sites in multiple cancer types. CONCLUSION:We have identified 368 DNA methylation changes that characterize breast cancer tumor tissue, of which 209 are associated with genes that are differentially-expressed in the same samples. Novel DNA methylation markers were identified, of which cg12374721 (PRAC2), cg18081940 (TDRD10) and cg04475027 (TMEM132C) show promise as diagnostic and prognostic markers in breast cancer as well as other cancer types.
DNA methylation mediated silencing of microRNA-874 is a promising diagnosis and prognostic marker in breast cancer.
Zhang Lei,Yan Da-Li,Yang Fan,Wang Dan-Dan,Chen Xiu,Wu Jian-Zhong,Tang Jin-Hai,Xia Wen-Jie
MicroRNA-874 (miR-874) is downregulated in several human cancers and has been suggested to be a tumor suppressor gene. However, the molecular mechanism of miR-874 downregulation in breast cancer has not been well elucidated. Here we aimed to study the aberrant hyper-methylation of CpG sites with the utility of miR-874 downreregulation in breast cancer and evaluate the clinical function of miR-874 as a prognostic marker. The miR-874 expressions in cells and tissues of two breast cancer lines were measured by real-time PCR. The DNA methylation status of the miR-874 promoter region in 19 pairs of breast cancer and adjacent normal samples was analyzed with Sequenom EpiTYPER MassArray. To evaluate whether miR-874 is a potential prognostic marker in breast cancer, we also explored the clinical long-time follow-up records from The Cancer Genome Atlas (TCGA). We found miR-874 expression was downregulated in 47 pairs of breast cancer tissues. Moreover, univariate and multivariate analysis revealed miR-874 expression may be a prognostic biomarker of overall survival in breast cancer patients. Preconditioning with 5-Aza-CdR in two cell lines elevated miR-874 expressions. The data from Sequenom EpiTYPER MassArray showed that DNA methylation of the promoter region of miR-874 was upregulated and accompanied by decreased miR-874 expression, which was further confirmed by TCGA. After comprehensive considerations, we think miR-874, which might be served as a prognostic biomarker, is mediated by DNA methylation.
Elevated miR-301a expression indicates a poor prognosis for breast cancer patients.
Zheng Jin-Zhou,Huang Yan-Ni,Yao Ling,Liu Yi-Rong,Liu Sheng,Hu Xin,Liu Zhe-Bin,Shao Zhi-Min
Although microRNA-301a (miR-301a) has been reported to function as an oncogene in many human cancers, there are limited data regarding miR-301a and breast tumours. In this study, we first detected the expression of miR-301a using an in situ hybridization (ISH) -based classification system in 380 samples of BC tissue, including both non-TNBC (triple-negative breast cancer) and TNBC specimens. Our results suggest that analysing miR-301a expression in breast tissue biopsy specimens at the time of diagnosis could have the potential to identify patients who might be candidates for active surveillance. We validated our results that higher expression of miR-301a is associated with a decreased OS in independent public breast cancer databases, such as TCGA and METABRIC, using the online webtool Kaplan-Meier Plotter, which provided additional powerful evidence to confirm the prognostic value of miR-301a. MiR-301a may serve as a potential therapeutic target for patients with breast cancer. According to our results, miR-301a should be considered, and novel therapeutic options are needed to target this aggressive miR-301a-positive type of breast cancer to reduce recurrence and the mortality rate.
Regulator of G protein signaling 20 correlates with clinicopathological features and prognosis in triple-negative breast cancer.
Li Quan,Jin Wenxu,Cai Yefeng,Yang Fang,Chen Endong,Ye Danrong,Wang Qingxuan,Guan Xiaoxiang
Biochemical and biophysical research communications
Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype lacking effective prognostic indicators or therapeutic targets. Therefore, finding a novel molecular biomarker for TNBC to achieve target therapy and predict its prognosis is crucial in preventing inappropriate treatment. Regulator of G-protein signaling (RGS) families of protein can negatively regulate signaling of heterotrimeric G proteins and are known to be upregulated in various tumors. In this study, we demonstrated that RGS20 was more highly expressed in TNBC tumor tissue than in adjacent normal tissue by analyzing the cancer genome atlas (TCGA) database. However, RGS20 expression was low in all breast cancer and luminal breast cancer patients. Validated by the TCGA cohort, RGS20 was upregulated in lymph node-positive TNBC compared with that in lymph node-negative breast cancer. High expression of RGS20 had a risk of lymph node metastasis, ki-67 > 14%, poor N stage, and poor clinical stage in the immunohistochemistry of tissue microarrays. Moreover, K-M plot analysis showed that TNBC patients with high RGS20 expression had poor relapse-free survival. In summary, the findings revealed that RGS20 was a special TNBC oncogene that promoted tumor progression and influenced TNBC prognosis. This study is the first to show that RGS20 was a special oncogene, and its high expression was significantly associated with the progression and prognosis of TNBC. RGS20 may be a novel molecular biomarker for the targeted therapy and prognosis of TNBC.
ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway.
Zhang Qi,Lu Sihong,Li Tianfu,Yu Liang,Zhang Yunjian,Zeng Huijuan,Qian Xueke,Bi Jiong,Lin Ying
Journal of experimental & clinical cancer research : CR
BACKGROUND:Breast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear. METHODS:The prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model. RESULTS:ACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs. CONCLUSIONS:Our findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway. TRIAL REGISTRATION:Retrospectively registered.
Clinicopathological and prognostic significance of Ras association and pleckstrin homology domains 1 (RAPH1) in breast cancer.
Kurozumi Sasagu,Joseph Chitra,Sonbul Sultan,Aleskandarany Mohammed A,Pigera Marian,Alsaleem Mansour,Alsaeed Sami,Kariri Yousif,Nolan Christopher C,Diez-Rodriguez Maria,Johnston Simon,Mongan Nigel P,Fujii Takaaki,Shirabe Ken,Martin Stewart G,Ellis Ian O,Green Andrew R,Rakha Emad A
Breast cancer research and treatment
BACKGROUND:Ras association and pleckstrin homology domains 1 (RAPH1) is involved in cytoskeleton regulation and re-epithelialisation in invasive carcinoma and, therefore, may play a key role in carcinogenesis and metastasis. We, herein, investigated the biological and clinical significance of RAPH1 in breast cancer using large annotated cohorts. METHODS:The clinicopathological and prognostic significance of RAPH1 was assessed at the genomic and transcriptomic levels using The Cancer Genome Atlas (TCGA) dataset (n = 1039) and the results were validated using the Molecular taxonomy of breast cancer international consortium (METABRIC) cohort (n = 1980). RAPH1 protein expression was evaluated by immunohistochemistry in a large, well-characterised cohort of early-stage breast cancer (n = 1040). RESULTS:In both the TCGA and METABRIC cohorts, RAPH1 mRNA expression and RAPH1 copy number alteration were strongly correlated. RAPH1 mRNA overexpression was significantly correlated with high expression of adhesion and EMT markers including CDH1, TGFβ1 and CD44. RAPH1 mRNA overexpression was a significant predictor of a poor prognosis (Hazard ratio 3.88; p = 0.049). High RAPH1 protein expression was associated with higher grade tumours with high proliferation index, triple negative phenotype and high E-cadherin expression. High RAPH1 protein expression was an independent predictor of shorter survival (Hazard ratio 4.37; p = 0.037). CONCLUSIONS:High RAPH1 expression is correlated with aggressive breast cancer phenotypes and provides independent prognostic value in invasive breast cancer.
How Young Is Too Young in Breast Cancer?-Young Breast Cancer Is Not a Unique Biological Subtype.
Fu Jianfei,Wu Lunpo,Fu Wei,Tan Yinuo,Xu Tiantian,Hong Zhongwu,Wang Fan,Li Shuguang
Clinical breast cancer
BACKGROUND:There is no uniformly adopted cutoff value to define "young patients" with breast cancer. This study was designed to determine an optimal cutoff value, to investigate prognostic factors and to explore gene expression profiles of young female breast cancer. MATERIALS AND METHODS:The Surveillance, Epidemiology, and End Results database was examined to identify cases of female breast cancer diagnosed between 2000 and 2007. The optimal cutoff value for young age was determined using the X-tile program (Yale University, version 3.6.1). Age-specific gene expression profiles were explored using RNA sequence data from the Cancer Genome Atlas database. RESULTS:The age of 40 years was determined as the optimal cutoff value. Among 94,087 patients, 12,755 were aged 40 years or younger (younger group), and 81,332 were older (older group). The 5- and 10-year cancer-specific survival rates in younger and older groups were 88.74% and 80.65%, respectively, and 93.22% and 88.43%, respectively (P < .001). Univariate and multivariate analyses indicated younger patients had worse prognosis. Subgroup analysis according to estrogen receptor (ER) showed the risk for cancer-specific death of ER-positive (ER) younger patients increased by approximately 2 times (hazard ratio, 1.96) compared with ER older patients. We failed to find any age-related gene in 509 patients after adjusting according to subtype (50-gene prediction analysis of a microarray) and histological type. CONCLUSION:The age of 40 years is a reasonable cutoff value for defining "young." Young patients with breast cancer, especially those in the ER subgroup, have worse prognosis. However, we found that young breast cancer is not a unique biological entity, and therefore, a lack of new potential targets.
Increased RNA Expression of von Willebrand Factor Gene Is Associated With Infiltrating Lobular Breast Cancer and Normal PAM50 Subtype.
Lehrer Steven,Green Sheryl,Dembitzer Francine R,Rheinstein Peter H,Rosenzweig Kenneth E
Cancer genomics & proteomics
BACKGROUND:Infiltrating lobular carcinoma (ILC) is the second most common histologicaI subtype of breast cancer, accounting for 10% of all cases. ILC has a characteristic genomic profile. ILC shows a high frequency of cadherin 1 (CDH1) mutations, along with loss of phosphatase and tensin homolog (PTEN), activation of alpha serine/threonine kinase (AKT), and mutations in T-box transcription factor (TBX3) and forkhead box protein A1 (FOXA1). We suspected that another gene, von Willebrand factor (VWF), might also be part of the profile, since coagulation tests reveal significant differences in patients with breast cancer. MATERIALS AND METHODS:For newly-diagnosed breast cancer, the association between VWF and histology in the GDC Breast Cancer dataset in The Cancer Genome Atlas (TCGA) was evaluated. The following were used to access and analyze the data: Genomic Data Commons Data Portal (https://portal.gdc.cancer.gov/); Xena browser (https://xenabrowser.net); cBioportal (http://cbioportal.org); Oncomine (https://oncomine.org); and Prediction Analysis of Microarray 50 (PAM50). RESULTS:Patients with ILC had higher VWF RNA expression than patients with infiltrating ductal carcinoma and other histology. The difference of expression was present to the same degree in both pre-menopausal and post-menopausal patients. Nine alterations in VWF and PTEN were significantly co-occurrent. Considering all histologies in 843 samples, Tukey's honest significant difference post hoc test showed that VWF RNA expression of the normal subtype was significantly greater than that of the other subtypes (p<0.001). CONCLUSION:Our finding of significantly higher VWF RNA expression in the PAM50 normal (non-basal-like) breast cancer subtype suggests that VWF protein measurement might complement or corroborate PAM50 results. VWF and PAM50 results both suggesting a low risk of recurrence might make the decision whether to give chemotherapy easier, especially if VWF protein were an independent predictor.
Angiopoietin pathway gene expression associated with poor breast cancer survival.
Ramanathan Rajesh,Olex Amy L,Dozmorov Mikhail,Bear Harry D,Fernandez Leopoldo Jose,Takabe Kazuaki
Breast cancer research and treatment
PURPOSE:Angiogenesis is one of the hallmarks of cancer and is essential for cancer progression and metastasis. However, clinical trials with vascular endothelial growth factor (VEGF) pathway inhibitors have failed to show overall survival benefit in breast cancer. Targeted therapy against the angiopoietin pathway, a downstream angiogenesis cascade, could be effective in breast cancer. This study investigates the association of angiopoietin pathway gene expression with breast cancer survival using a "big data" approach employing RNA sequencing data from The Cancer Genome Atlas (TCGA). METHODS:A total of 888 patients with adequate gene expression, disease-free survival (DFS), and overall survival (OS) data were selected for analysis. DFS and OS were calculated for patients with high and low expression of angiopoietin and VEGF pathway genes using TCGA data. Gene-specific thresholds to dichotomize patients into high and low expression were determined and survival plots were generated. RESULTS:The TCGA cohort was representative of national breast cancer patients with respect to stage, pathology, and survival. High Ang2 gene expression was associated with not only decreased DFS (p = 0.05), but also decreased OS (p < 0.05). High co-expression of Ang2 and its receptor Tie2 was associated with both decreased DFS and OS (p < 0.05). There was strong correlation between angiopoietin and VEGF pathway genes. While high expression of VEGFA alone was not associated with survival, high co-expression with Ang2 was associated with decreased OS. CONCLUSIONS:This study validates TCGA as a representative database providing genomic data and survival outcomes in breast cancer. Our TCGA data support the angiopoietin pathway as a key mediator in the pathologic angiogenic switch in breast cancer.
GTSE1 is involved in breast cancer progression in p53 mutation-dependent manner.
Lin Fen,Xie Yu-Jie,Zhang Xin-Ke,Huang Tie-Jun,Xu Hong-Fa,Mei Yan,Liang Hu,Hu Hao,Lin Si-Ting,Luo Fei-Fei,Lang Yan-Hong,Peng Li-Xia,Qian Chao-Nan,Huang Bi-Jun
Journal of experimental & clinical cancer research : CR
BACKGROUND:With the rapid development of the high throughput detection techniques, tumor-related Omics data has become an important source for studying the mechanism of tumor progression including breast cancer, one of the major malignancies worldwide. A previous study has shown that the G2 and S phase-expressed-1 (GTSE1) can act as an oncogene in several human cancers. However, its functional roles in breast cancer remain elusive. METHOD:In this study, we analyzed breast cancer data downloaded from The Cancer Genome Atlas (TCGA) databases and other online database including the Oncomine, bc-GenExMiner and PROGgeneV2 database to identify the molecules contributing to the progression of breast cancer. The GTSE1 expression levels were investigated using qRT-PCR, immunoblotting and IHC. The biological function of GTSE1 in the growth, migration and invasion of breast cancer was examined in MDA-MB-231, MDA-MB-468 and MCF7 cell lines. The in vitro cell proliferative, migratory and invasive abilities were evaluated by MTS, colony formation and transwell assay, respectively. The role of GTSE1 in the growth and metastasis of breast cancer were revealed by in vivo investigation using BALB/c nude mice. RESULTS:We showed that the expression level of GTSE1 was upregulated in breast cancer specimens and cell lines, especially in triple negative breast cancer (TNBC) and p53 mutated breast cancer cell lines. Importantly, high GTSE1 expression was positively correlated with histological grade and poor survival. We demonstrated that GTSE1 could promote breast cancer cell growth by activating the AKT pathway and enhance metastasis by regulating the Epithelial-Mesenchymal transition (EMT) pathway. Furthermore, it could cause multidrug resistance in breast cancer cells. Interestingly, we found that GTSE1 could regulate the p53 function to alter the cell cycle distribution dependent on the mutation state of p53. CONCLUSION:Our results reveal that GTSE1 played a key role in the progression of breast cancer, indicating that GTSE1 could serve as a novel biomarker to aid in the assessment of the prognosis of breast cancer.
Young age at diagnosis is associated with worse prognosis in the Luminal A breast cancer subtype: a retrospective institutional cohort study.
Liu Zhiyang,Sahli Zeyad,Wang Yongchun,Wolff Antonio C,Cope Leslie M,Umbricht Christopher B
Breast cancer research and treatment
PURPOSE:Although age is a recognized independent prognostic risk factor, its relative importance among molecular subtypes of Breast cancer (BCA) is not well documented. The aim of this study was to evaluate the prognostic role of age at diagnosis among different immunohistochemical subtypes of BCA. METHODS:We conducted a retrospective study of women with invasive BCA undergoing surgery at the Johns Hopkins Hospital, excluding patients presenting with stage IV breast cancer. Patients were stratified into three age groups: ≤ 40, 41-60, and > 60 years, and multivariable analysis was performed using Cox regression. We also identified differentially expressed genes (DEG) between age groups among BCA subtypes in the public TCGA dataset. Finally, we identified key driver genes within the DEGs using a weighted gene co-expression network analysis. RESULTS:Luminal A breast cancer patients had significantly lower 5 year disease-free survival (DFS) and distant metastasis-free survival (DMFS) in the ≤ 40 year age group compared to the 41-60 year age group, while the other molecular subtypes showed no significant association of DFS or DMFS with age. Age was a stronger outcome predictor than tumor grade or proliferative index in Luminal A BCA patients, but not other subtypes. BCA TCGA gene expression data were divided into two groups (≤ 40 years, > 40 years). We identified 374 DEGs in the Luminal A BCA subset, which were enriched in seven pathways and two modules of co-expressed genes. No age group-specific DEGs were identified in non-Luminal A subtypes. CONCLUSIONS:Age at diagnosis may be an important prognostic factor in Luminal A BCA.
Co-expression network analysis identified candidate biomarkers in association with progression and prognosis of breast cancer.
Zhou Qiang,Ren Jiangbo,Hou Jinxuan,Wang Gang,Ju Lingao,Xiao Yu,Gong Yan
Journal of cancer research and clinical oncology
PURPOSE:Breast cancer is one of the most common malignancies among females, and its prognosis is affected by a complex network of gene interactions. Weighted gene co-expression network analysis was used to construct free-scale gene co-expression networks and to identify potential biomarkers for breast cancer progression. METHODS:The gene expression profiles of GSE42568 were downloaded from the Gene Expression Omnibus database. RNA-sequencing data and clinical information of breast cancer from TCGA were used for validation. RESULTS:A total of ten modules were established by the average linkage hierarchical clustering. We identified 58 network hub genes in the significant module (R = 0.44) and 6 hub genes (AGO2, CDC20, CDCA5, MCM10, MYBL2, and TTK), which were significantly correlated with prognosis. Receiver-operating characteristic curve validated that the mRNA levels of these six genes exhibited excellent diagnostic efficiency in the test data set of GSE42568. RNA-sequencing data from TCGA showed that the expression levels of these six genes were higher in triple-negative tumors. One-way ANOVA suggested that these six genes were upregulated at more advanced stages. The results of independent sample t test indicated that MCM10 and TTK were associated with tumor size, and that AGO2, CDC20, CDCA5, MCM10, and MYBL2 were overexpressed in lymph-node positive breast cancer. CONCLUSIONS:AGO2, CDC20, CDCA5, MCM10, MYBL2, and TTK were identified as candidate biomarkers for further basic and clinical research on breast cancer based on co-expression analysis.
Novel MicroRNA-Based Risk Score Identified by Integrated Analyses to Predict Metastasis and Poor Prognosis in Breast Cancer.
Kawaguchi Tstutomu,Yan Li,Qi Qianya,Peng Xuan,Edge Stephen B,Young Jessica,Yao Song,Liu Song,Otsuji Eigo,Takabe Kazuaki
Annals of surgical oncology
BACKGROUND:The use of biomarkers that allow early therapeutic intervention or intensive follow-up evaluation is expected to be a powerful means for reducing breast cancer mortality. MicroRNAs (miRNAs) are known to play major roles in cancer biology including metastasis. This study aimed to develop a novel miRNA risk score to predict patient survival and metastasis in breast cancer. METHODS:An integrated unbiased approach was applied to derive a composite risk score for prognosis based on miRNA expression in primary breast tumors in 1051 breast cancer patients from The Cancer Genome Atlas (TCGA). Further analysis of the risk score with metastasis/recurrence was performed using the TCGA data set and validated in a separate patient population using small RNA sequencing. RESULTS:The three-miRNAs risk score (miR-19a, miR-93, and miR-106a) was developed using the TCGA cohort, which predicted poor prognosis (p = 0.0005) independently of known clinical risk factors. The prognostic value was validated in another three following independent cohorts: GSE19536 (p = 0.0009), GSE22220 (p = 0.0003), and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (p = 0.0023). The three-miRNAs risk score predicted bone recurrence in TCGA (p = 0.0052), and the findings were validated in another independent population of patients who experienced bone recurrence and age/stage-matched patients without any recurrence. The three-miRNAs risk score enriched multiple metastasis-related gene sets such as angiogenesis and epithelial mesenchymal transition in a gene-set-enrichment analysis. CONCLUSIONS:The authors developed the novel miRNA-based risk score, which is a promising biomarker for prediction of worse survival and bone recurrence potential in breast cancer.
Identification of key genes relevant to the prognosis of ER-positive and ER-negative breast cancer based on a prognostic prediction system.
Xiao Bin,Hang Jianfeng,Lei Ting,He Yongyin,Kuang Zhenzhan,Wang Li,Chen Lidan,He Jia,Zhang Weiyun,Liao Yang,Sun Zhaohui,Li Linhai
Molecular biology reports
Few prognostic indicators with differential expression have been reported among the differing ER statuses. We aimed to screen important breast cancer prognostic genes related to ER status and to construct an efficient prognostic prediction system. mRNA expression profiles were downloaded from TCGA and GSE70947 dataset. Two hundred seventy-one overlapping differentially expressed genes (DEGs) between the ER- and ER+ breast cancer samples were identified. Among the 271 DEGs, 109 prognostically relevant mRNAs were screened. mRNAs such as RASEF, ITM2C, CPEB2, ESR1, ANXA9, and VASN correlated strongly with breast cancer prognosis. Three modules, which contained 28, 9 and 8 enriched DEGs, were obtained from the network, and the DEGs in these modules were enriched in response to hormone stimulus, epithelial cell development, and host cell entry. Using bayes discriminant analysis, 48 signature genes were screened. We constructed a prognostic prediction system using the 48 signature genes and validated this system as relatively accurate and reliable. The DEGs might be closely associated with the prognosis in patients with breast cancer. We validated the effectiveness of our prognostic prediction system by GEO database. Therefore, this system might be a useful tool for preliminary screening and validation of potential prognosis indicators for ER+ breast cancer derived from mechanistic research.