FKBPL: a marker of good prognosis in breast cancer.
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ABSTRACT:
SUBMITTER: Nelson L
PROVIDER: S-EPMC4494933 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hypoxia and pH influence gene expression in tumours, and it is becoming increasingly clear that the pattern of genes expressed by a tumour determines its growth and survival characteristics. Hypoxia-inducible factor-1 (HIF-1) is a key mediator of the cellular response to hypoxia and high HIF-1 expression has been identified as a poor prognostic factor in tumours. Recently, we identified the tumour-associated carbonic anhydrases (CA), CA9 and CA12 as hypoxia-inducible in tumour cell lines. Furthermore, we identified CA IX to be a poor prognostic factor in breast cancer. The aim of this study was to assess the prognostic significance of CA XII. CA XII expression was studied by immunohistochemistry in a series of 103 cases of invasive breast cancer and any association with recognised prognostic factors or relation with the outcome was examined. CA XII expression was present in 77 out of 103 (75%) cases and was associated with lower grade (P=0.001), positive estrogen receptor status (P<0.001), and negative epidermal growth factor receptor status (P<0.001). Furthermore, although CA XII expression was associated with an absence of necrosis (P<0.001), expression of CA XII in some high-grade tumours was induced in regions directly adjacent to morphological necrosis. Additionally, using univariate analysis, CA XII positive tumours were associated with a lower relapse rate (P=0.04) and a better overall survival (P=0.01). In conclusion, CA XII expression is influenced both by factors related to differentiation and hypoxia in breast cancer in vivo and CA XII expression is associated with a better prognosis in an unselected series of invasive breast carcinoma patients.
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Project description:The mitogen-activated protein kinase/extracellular signal-regulated (MAPK/ERK) pathway is a well-characterized signaling pathway during the development of various cancer types. ERK1 and ERK2, the two kinase effectors of MAPK cascade, exhibit high similarity. However, it is still unknown whether these two kinases are functionally different or in contrast functionally redundant during the development of breast cancer. We found that ERK1 expression levels were significantly lower in basal breast cancer compared with luminal breast cancer and normal breast tissues. RNA sequencing data suggested that ERK1 was associated with Hippo signaling pathway and cell proliferation in breast cancer cells. The gene set enrichment analysis (GSEA) further showed enrichment for YAP1 signaling pathway in breast cancer cell lines and tumors with low expression of ERK1. Silencing of ERK1 elevated YAP1 expression and TEAD activity in breast cancer cells. Additionally, ERK1 inhibited breast cancer cell proliferation via regulation of YAP1. The Kaplan-Meier analysis of data in patients with breast cancer suggested that, higher expression of ERK1 was associated with better prognosis, whereas, higher expression of ERK2 predicted poorer prognosis. These findings unveiled the role of ERK1 on regulation of YAP1 signaling pathway, indicating ERK1 as a negative regulator of breast cancer progression.
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Project description:PurposeThe outcome of the luminal oestrogen receptor-positive (ER +) subtype of breast cancer (BC) is highly variable and patient stratification needs to be refined. We assessed the prognostic significance of oestrogen-regulated solute carrier family 39 member 6 (SLC39A6) in BC, with emphasis on ER + tumours.Materials and methodsSLC39A6 mRNA expression and copy number alterations were assessed using the METABRIC cohort (n = 1980). SLC39A6 protein expression was evaluated in a large (n = 670) and annotated series of early-stage (I-III) operable BC using tissue microarrays and immunohistochemistry. The associations between SLC39A6 expression and clinicopathological parameters, patient outcomes and other ER-related markers were evaluated using Chi-square tests and Kaplan-Meier curves.ResultsHigh SLC39A6 mRNA and protein expression was associated with features characteristic of less aggressive tumours in the entire BC cohort and ER + subgroup. SLC39A6 protein expression was detected in the cytoplasm and nuclei of the tumour cells. High SLC39A6 nuclear expression and mRNA levels were positively associated with ER + tumours and expression of ER-related markers, including the progesterone receptor, forkhead box protein A1 and GATA binding protein 3. In the ER + luminal BC, high SLC39A6 expression was independently associated with longer BC-specific survival (BCSS) (P = 0.015, HR 0.678, 95% CI 0.472‒0.972) even in those who did not receive endocrine therapy (P = 0.001, HR 0.701, 95% CI 0.463‒1.062).ConclusionSLC39A6 may be prognostic for a better outcome in ER + luminal BC. Further functional studies to investigate the role of SLC39A6 in ER + luminal BC are warranted.
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Project description:IntroductionNormal function of the p53 network is lost in most cancers, often through p53 mutation. The clinical impact of p53 mutations in breast cancer remains uncertain, especially where p53 isoforms may modify the effects of these p53 mutations.MethodsExpression of p53? and p53? isoforms, the isoforms identified in normal breast tissue, was detected by reverse transcription polymerase chain reaction from a cohort of 127 primary breast tumours. Expression of p53? and p53? isoforms was analysed in relation to clinical markers and clinical outcomes (5 years) by binary logistic regression, Cox proportional hazards regression and Kaplan-Meier survival analyses.Resultsp53? and p53? were not randomly expressed in breast cancer. p53? was associated with tumour oestrogen receptor (ER) expression, and p53? was associated with mutation of the p53 gene. The patient group with the mutant p53 breast tumour-expressing p53? isoform had low cancer recurrence and an overall survival as good as that of patients with wild-type p53 breast cancer. Conversely, patients expressing only mutant p53, without p53? isoform expression, had a particularly poor prognosis.ConclusionsThe determination of p53? expression may allow the identification, independently of the ER status, of two subpopulations of mutant p53 breast cancer patients, one expressing p53? with a prognosis as good as the wild-type p53 breast cancer patients and a second one not expressing p53? with a particularly poor prognosis. The p53? isoform may provide an explanation of the hitherto inconsistent relationship between p53 mutation, treatment response and outcome in breast cancer.
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Project description:The study entails novel bio-marker discovery of Tumor Aggressive Grade signature (TAGs) genes and their role in recurrence free survival of breast cancer (BC) patients. Current BC dataset was used for co-expression analysis of TAGs genes and their role in BC progression. Additionally, recent findings have suggested an importance of structural organization of sense-antisense gene pairs (SAGPs) for transcription, post-transcriptional and post-translational events and their associations with cancer and disease. We studied SAGPs in which both gene partners are protein encoding genes (coding-coding SAGPs, ccSAGPs), their role in human BC development and demonstrated their potential for BC stratification and prognosis. Based on gene expression and correlation analyses we identified the robust set of breast cancer-relevant ccSAGPs (BCR-ccSAGPs). We isolated and characterized the sense-antisense gene classifier (SAGC) and evaluated its prognostic potential in various gene expression datasets comprising 1161 BC patients. The methods used included the Cox proportional survival analysis, statistical analysis of clinicopathologic parameters and differential gene expression.The SAGC was effective in identification of BC patients with the most aggressive disease. Independently, we validated the SAGC using 58 RNA samples of breast cancer tumors purchased from OriGene Technologies (Rockville, MD). Sixty two total RNA samples from breast tumors and normal breast epithelium have been purchased from OriGene Technologies in March, 2011. Four RNA samples were obtained from normal individuals. Among 58 breast tumors (58 patients) 56 were diagnosed as ductal breast adenocarcinoma, 1 - as lobular breast adenocarcinoma and 1 - as squamous cell carcinoma. Gene expression data for all the samples were quantified by using whole-genome RNA microarrays (HG-U133 plus 2.0, Affymetrix).
2015-05-10 | E-GEOD-61304 | biostudies-arrayexpress
Project description:The study entails novel bio-marker discovery of Tumor Aggressive Grade signature (TAGs) genes and their role in recurrence free survival of breast cancer (BC) patients. Current BC dataset was used for co-expression analysis of TAGs genes and their role in BC progression. Additionally, recent findings have suggested an importance of structural organization of sense-antisense gene pairs (SAGPs) for transcription, post-transcriptional and post-translational events and their associations with cancer and disease. We studied SAGPs in which both gene partners are protein encoding genes (coding-coding SAGPs), their role in human BC development and demonstrated their potential for BC stratification and prognosis. Based on gene expression and correlation analyses we identified the robust set of breast cancer-relevant SAGPs (BCR-SAGPs). We isolated and characterized the sense-antisense gene signature (SAGS) and evaluated its prognostic potential in various gene expression datasets comprising 1161 BC patients. The methods used included the Cox proportional survival analysis, statistical analysis of clinicopathologic parameters and differential gene expression. The SAGS was effective in identification of BC patients with the most aggressive disease. Independently, we validated the SAGS using 58 RNA samples of breast cancer tumors purchased from OriGene Technologies (Rockville, MD).
2015-05-10 | GSE61304 | GEO
Project description:PurposeMicroRNAs can influence many biological processes and have shown promise as cancer biomarkers. Few studies have focused on the expression of microRNA-223 (miR-223) and its precise role in breast cancer (BC). We aimed to examine the expression level of miR-223 and its prognostic value in BC.MethodsTissue microarray (TMA)-based miRNA detection in situ hybridization (ISH) with a locked nucleic acid (LNA) probe was used to detect miR-223 expression in 450 BC tissue samples. Overall survival (OS) and disease-free survival (DFS) were compared between two groups using the Kaplan-Meier method and Cox regression model.ResultsOS and DFS were prolonged in the high miR-223 expression group compared to the low miR-223 expression group (p < 0.0001 and p = 0.017, respectively), especially in patients with the triple-negative breast cancer (TNBC) subtype (p = 0.046 and p < 0.001, respectively). Univariate and multivariate Cox regression analyses revealed that TNM stage (p = 0.008), the molecular subtype (p = 0.049), and miR-223 (p < 0.001) were independently associated with OS and DFS. External validation was performed with the METABRIC and The Cancer Genome Atlas (TCGA) databases via online webtools and was consistent with the data described above.ConclusionsThis study provides evidence that high miR-223 expression at diagnosis is associated with improved DFS and OS for BC patients, especially those with the TNBC subtype. miR-223 is a valid and independent prognostic biomarker in BC.
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Project description:Background: Breast cancer is a pivotal cause of global women cancer death. Immunotherapy has become a promising means to cure breast cancer. As constitutes of immune microenvironment of breast cancer, macrophages exert complicated functions in the tumour development and treatment. This study aims to develop a prognostic macrophage marker genes signature (MMGS).Methods: Single cell RNA sequence data analysis was performed to identify macrophage marker genes in breast cancer. TCGA database was used to construct MMGS model as a training cohort, and GSE96058 dataset was used to validate the MMGS as a validation cohort.Results: Genes included in the MMGS model were: SERPINA1, CD74, STX11, ADAM9, CD24, NFKBIA, PGK1. MMGS risk score stratified by overall survival of patients divided them into high- and low-risk groups. And MMGS risk score remained independent prognostic factor in multivariate analysis after adjusting for classical clinical factors in both training and validation cohorts. Besides, hormone receptors negative and human epidermal growth factor receptor 2 (HER2) positive patients had higher risk score. MMGS showed better distinguishing capability between high-risk and low-risk groups in hormone receptor positive and HER2 negative subgroup.Conclusion: MMGS provides a new understanding of immune cell marker genes in breast cancer prognosis and may offer reference for immunotherapy decision for breast cancer patients.
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Project description:Cytosine deamination to uracil in DNA leads to mutations if the DNA lesion is not corrected. Base excision repair (BER) initiated by single-strand selective uracil-DNA glycosylase 1 (SMUG1) primarily recognizes uracil and oxidized pyrimidines, and processes them to restore the correct bases. SMUG1 status has been associated with cancer risk and therapeutic response as high levels of SMUG1 were observed in breast carcinomas and other cancer types. The role of SMUG1 in breast cancer is not completely understood. Here, we define a bad prognosis signature for SMUG1 interactors in different cancers by mapping out a SMUG1 interaction network. Survival analyses of patient outcomes show that high expression of genes in the bad prognosis network correlates with lower survival probability in breast cancer. Interestingly, bioinformatics analyses suggested let-7b-5p microRNA as one of the upstream regulators of SMUG1 interactors. Expression of SMUG1 and let-7b-5p are negatively correlated in breast cancer and we observed an inhibitory auto-regulatory loop between SMUG1 and let-7b-5p in MCF-7 cells. Hence, SMUG1 is a key player connecting RNA and DNA metabolism with regulation of gene expression.
2023-03-09 | PXD025929 | Pride