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The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer.

ABSTRACT: Mounting evidence suggests that neuronal PAS domain protein 2 (NPAS2) and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. The current study further examined the prognostic significance of NPAS2 in breast cancer by genotyping the Ala394Thr polymorphism and measuring NPAS2 expression. DNA extracted from 348 breast cancer tissue samples was analyzed for NPAS2 genotype using the TaqMan allelic discrimination assay. Of these, 287 also had total RNA available for use in real-time PCR assays to determine NPAS2 expression. NPAS2 genotypes and expression levels were analyzed for associations with prognostic outcomes, as well as correlations with clinical characteristics. A high level of NPAS2 expression was strongly associated with improved disease free survival (AHR = 0.43, 95% CI: 0.21-0.86, P trend = 0.022) and overall survival (AHR = 0.42, 95% CI: 0.19-0.96, P trend = 0.036). In addition, there was a borderline, but nonsignificant association between the NPAS2 genotype corresponding to Thr394Thr and disease free survival (AHR = 1.82, 95% CI: 0.96-3.46). The Ala/Ala, Ala/Thr, and Thr/Thr genotypes were also differentially distributed by tumor severity, as measured by TNM classification (chi (2) (6df, N = 344) = 14.96, P = 0.020). These findings provide the first evidence suggesting prognostic significance of the circadian gene NPAS2 in breast cancer.

SUBMITTER: Yi C

PROVIDER: S-EPMC3108061 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer.

Yi Chunhui C Mu Lina L de la Longrais Irene A Rigault IA Sochirca Olga O Arisio Riccardo R Yu Herbert H Hoffman Aaron E AE Zhu Yong Y Katsaro Dionyssios D

Breast cancer research and treatment 20090801 3

Mounting evidence suggests that neuronal PAS domain protein 2 (NPAS2) and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. The current study further examined the prognostic significance of NPAS2 in breast cancer by genotyping the Ala394Thr polymorphism and measuring NPAS2 expression ...[more]

PMID: 19649706

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Project description:BackgroundRecQ-mediated genome instability 2 (RMI2) maintains genome stability by promoting DNA damage repair. It has been reported to accelerate the progression of several tumors. However, the functional mechanism of RMI2 in breast cancer remains unclear.MethodsGene expression profiles were obtained from TCGA, GTEx, and GEO databases. The expression of RMI2 and its prognostic value in breast cancer was explored. In addition, we calculated pooled standardized mean deviation (SMD) and performed a summary receiver operating characteristic (sROC) curve analysis to further determine RMI2 expression status and diagnostic significance. The functions and related signaling pathways were investigated based on GO and KEGG analyses. The PPI network was constructed by combining the STRING database and Cytoscape software. Subsequently, in vitro assays were conducted to detect the effect of RMI2 on the proliferation and migration of breast cancer cells.ResultsThe expression of RMI2 was markedly upregulated in breast cancer tissues relative to that in normal tissues. Moreover, pooled SMD further confirmed the overexpression of RMI2 in breast cancer (SMD = 1.29, 95% confidence interval (CI): 1.18-1.41, p = 0.000). The sROC curve analysis result suggested that RMI2 had a relatively high diagnostic ability in breast cancer (AUC = 0.87, 95% CI: 0.84-0.90). High RMI2 expression was associated with poor prognosis. GO and KEGG analyses revealed that RMI2 was closely related to cell adhesion, various enzyme activities, and PI3K/AKT signaling pathway. PPI analysis showed that RMI2 had interactions with proteins involved in DNA damage repair. knockdown of RMI2 remarkably inhibited the proliferation and migration of breast cancer cells, while overexpression of RMI2 exerted the opposite effects. Furthermore, we identified that RMI2 accelerates the proliferation and migration of breast cancer cells via activation of the PI3K/AKT pathway.ConclusionThe results suggest that RMI2 is a potential diagnostic and prognostic biomarker associated with cell proliferation and migration, and may be used as a novel therapeutic target for breast cancer in the future.

Project description:Breast cancer is the most common cancer type and cause of cancer-related mortality among women worldwide. New biomarker discovery is crucial for diagnostic innovation and personalized medicine in breast cancer. Heat shock proteins (HSPs) have been increasingly reported as biomarkers and potential drug targets for cancers. HLJ1 (DNAJB4) belongs to the DNAJ (HSP40) family of HSPs and is regarded as a tumor suppressor gene in lung, colon, and gastric cancers. However, the role of the HLJ1 gene in breast cancer is currently unknown. We evaluated the role of the HLJ1 gene in breast cancer progression by analyzing its in vitro and in vivo expression and its genetic/epigenetic alterations. HLJ1 expression was found to be reduced or lost in breast cancer cell lines (SK-BR-3, MDA-MB-231, ZR-75-1) compared with the nontumorigenic mammary epithelial cell line (MCF 10A). In a clinical context for breast cancer progression, the HLJ1 expression was significantly less frequent in invasive breast carcinoma samples (n = 230) compared with normal breast tissue (n = 100), benign neoplasia (n = 53), and ductal carcinoma in situ (n = 21). In methylation analyses by the combined bisulfite restriction analysis assay, the CpG island located in the 5'-flanking region of the HLJ1 gene was found to be methylated in breast cancer cell lines. HLJ1 expression was restored in the ZR-75-1 cell line by DNA demethylating agent 5-Aza-2'-deoxycytidine (5-AzadC) and histone deacetylase inhibitor trichostatin A. These new observations support the idea that HLJ1 is a tumor suppressor candidate and potential biomarker for breast cancer. Epigenomic mechanisms such as CpG methylation and histone deacetylation might contribute to downregulation of HLJ1 expression. We call for future functional, epigenomic, and clinical studies to ascertain the contribution of HLJ1 to breast cancer pathogenesis and, importantly, evaluate its potential for biomarker development in support of personalized medicine diagnostic innovation in clinical oncology.

Project description:PURPOSE:This study evaluates the prognostic significance of MST1R (RON) expression in breast cancer with respect to disease progression, long-term survival, subtype, and association with conventional prognostic factors. METHODS:The approach includes interrogation of survival and tumor staging with paired MST1R RNA expression from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Protein expression evaluation was performed using immunohistochemistry (IHC) staining of MST1R on breast cancer tissue samples from the Cancer Diagnosis Program Breast Cancer Progression tissue microarray and locally obtained breast tumor tissue samples analyzed with paired survival, metastasis, and subtype. RESULTS:Data from TCGA (n?=?774) show poorer relapse-free survival (RFS) in patients with high MST1R expression (P?=?0.32) and no difference in MST1R expression based on tumor stage (P?=?0.77) or nodal status (P?=?0.94). Patients in the GEO-derived Kaplan-Meier Plotter microarray dataset demonstrate the association of MST1R and poorer overall survival (n?=?1402, P?=?0.018) and RFS in patients receiving chemotherapy (n?=?798, P?=?0.041). Patients with high MST1R expression display worse overall survival (P?=?0.01) and receiver operator characteristic (ROC) analysis demonstrate the predictive capacity of increased MST1R with early death (P?=?0.0017) in IHC-stained samples. Paired IHC-stained breast tumor samples from the primary versus metastatic site show MST1R expression is associated with metastatic progression (P?=?0.032), and ROC analysis supports the predictive capacity of MST1R in metastatic progression (P?=?0.031). No associations of MST1R with estrogen receptor (ER), progesterone receptor (PR), both ER and PR, HER2 positivity, or triple-negativity were found (P?=?0.386, P?=?0.766, P?=?0.746, P?=?0.457, P?=?0.947, respectively). CONCLUSIONS:MST1R expression has prognostic value in breast cancer with respect to survival and metastatic progression. MST1R expression is not associated with tumor stage, nodal status, or subtype.

Project description:BackgroundMore and more evidence suggests that cancer is a mitochondrial metabolic disease recently and mitochondria dysfunction is critical to tumorigenesis. As a gatekeeper of mitochondria, the voltage-dependent anion channel 1 (VDAC1) is associated with the development of breast cancer (BC). However, its potential mechanism and clinical significance remain unclear; thus, in this research, we aimed to explore it.MethodsVDAC1 expression in BC tissues and normal tissues was obtained from The Cancer Genome Atlas (TCGA) and validated by datasets from the gene expression omnibus (GEO) database. Then, the relationships between VDAC1 expression and clinicopathological features were analyzed. Receiver operating characteristics (ROC) curves were used to identify the diagnostic value of VDAC1. The prognostic value was evaluated by Kaplan-Meier survival curves and Cox regression analysis. VDAC1 with its co-expression genes were subjected to enrichment analysis to explore potential mechanisms in BC and the protein-protein interaction (PPI) network was constructed. At last, the association between VDAC1 expression and infiltration levels of immune cell infiltration by various methods, as well as their corresponding markers, was analyzed. We also analyzed the correction between VDAC1 expression and eight immune checkpoint genes and the tumor immune dysfunction and exclusion (TIDE) scores of each BC sample in TCGA were calculated and the differences between high and low VDAC1 expression groups were analyzed.ResultsVDAC1 expression was remarkably elevated in BC (p < 0.001), and high expression of VDAC1 was associated with the positive expression of ER (p = 0.004), PR (p = 0.033), and HER2 (p = 0.001). ROC analysis suggested that VDAC1 had diagnosed value in BC. The Kaplan-Meier analysis suggested that higher expression of VDAC1 was associated with shorter overall survival (OS), and further Cox regression analysis revealed that VDAC1 was an independent factor of unfavorable prognosis in BC patients. Enrichment analysis of VDAC1 and its co-expression suggested that VDAC1 was related to the regulation of mitochondrial energy metabolism and protein modification, and the HIF-1 singing pathway might be the potential mechanism in BC. Notably, we found that VDAC1 expression was infiltration levels of most types of immune cells, as well as the expression of marker genes of immune cells. The ICGs PDCD1, CTLA4, LAG3, SIGLEC15, and TIGIT were negatively corrected with VDAC1 expression in BC. TIDE scores between the low and high expression groups showed no difference.ConclusionOverexpressed VDAC1 in BC could be severed as a novel biomarker for diagnosis and VDAC1 was an independent factor for adverse prognosis prediction. Our study revealed that VDAC1 might inhibit tumor immunity and might be a novel therapeutic target in BC.

Project description:BackgroundThe clinical outcome of triple-negative breast cancer (TNBC) is poor. Finding more targets for the treatment of TNBC is an urgent need. SENPs are SUMO-specific proteins that play an important role in SUMO modification. Among several tumor types, SENPs have been identified as relevant biomarkers for progression and prognosis. The role of SENPs in TNBC is not yet clear.MethodsThe expression and prognosis of SENPs in TNBC were analyzed by TCGA and GEO data. SENP3 coexpression regulatory networks were determined by weighted gene coexpression network analysis (WGCNA). Least absolute shrinkage and selection operator (LASSO) and Cox univariate analyses were used to develop a risk signature based on genes associated with SENP3. A time-dependent receiver operating characteristic (ROC) analysis was employed to evaluate a risk signature's predictive accuracy and sensitivity. Moreover, a nomogram was constructed to facilitate clinical application.ResultsThe prognostic and expression effects of SENP family genes were validated using the TCGA and GEO databases. SENP3 was found to be the only gene in the SENP family that was highly expressed and associated with an unfavorable prognosis in TNBC patients. Cell functional experiments showed that knockdown of SENP3 leads to growth, invasion, and migration inhibition of TNBC cells in vitro. By using WGCNA, 273 SENP3-related genes were identified. Finally, 11 SENP3-related genes were obtained from Cox univariate analysis and LASSO regression. Based on this, a prognostic risk prediction model was established. The risk signature of SENP3-related genes was verified as an independent prognostic marker for TNBC patients.ConclusionAmong SENP family genes, we found that SENP3 was overexpressed in TNBC and associated with a worse prognosis. SENP3 knockdown can inhibit tumor proliferation, invasion, and migration. In TNBC patients, a risk signature based on the expression of 11 SENP3-related genes may improve prognosis prediction. The established risk markers may be promising prognostic biomarkers that can guide the individualized treatment of TNBC patients.

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The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer.

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The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer.

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