Dataset Information

Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes.

ABSTRACT: Signal transducer and activator of transcripton-5a (Stat5a) and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a/b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential association with clinical outcome.Stat5a and Stat5b protein levels were quantified in situ in breast-cancer progression material. Stat5a and Stat5b transcript levels in breast cancer were correlated with clinical outcome in 936 patients. Stat5a protein was further quantified in four archival cohorts totaling 686 patients with clinical outcome data by using multivariate models.Protein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared with normal epithelia. Low tumor levels of Stat5a but not Stat5b mRNA were associated with poor prognosis. Experimentally, only limited overlap between Stat5a- and Stat5b-modulated genes was found. In two cohorts of therapy-naïve, node-negative breast cancer patients, low nuclear Stat5a protein levels were an independent marker of poor prognosis. Multivariate analysis of two cohorts treated with antiestrogen monotherapy revealed that low nuclear Stat5a levels were associated with a more than fourfold risk of unfavorable outcome.Loss of Stat5a represents a new independent marker of poor prognosis in node-negative breast cancer and may be a predictor of response to antiestrogen therapy if validated in randomized clinical trials.

SUBMITTER: Peck AR

PROVIDER: S-EPMC4053108 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes.

Peck Amy R AR Witkiewicz Agnieszka K AK Liu Chengbao C Klimowicz Alexander C AC Stringer Ginger A GA Pequignot Edward E Freydin Boris B Yang Ning N Ertel Adam A Tran Thai H TH Girondo Melanie A MA Rosenberg Anne L AL Hooke Jeffrey A JA Kovatich Albert J AJ Shriver Craig D CD Rimm David L DL Magliocco Anthony M AM Hyslop Terry T Rui Hallgeir H

Breast cancer research : BCR 20121004 5

<h4>Introduction</h4>Signal transducer and activator of transcripton-5a (Stat5a) and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a/b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential associatio ...[more]

PMID: 23036105

Similar Datasets

Project description:BACKGROUND:Previously, we performed analysis of gene expression in 46 axillary lymph node negative tumors and identified molecular gene signatures that resulted in different clinical outcomes. The aim of this study was to determine the correlation of ?-glutamyl hydrolase (GGH), fatty acid amide hydrolase (FAAH), Pirin (PIR) and TAF5-like RNA polymerase II, p300/CBP-associated factor (PCAF)-associated factor, 65 kDa (TAF5L), selected from identified gene signatures, with clinical outcomes as well as classical clinicopathological characteristics in primary invasive breast cancer patients. METHODS:The protein levels of GGH, FAAH, PIR and TAF5L were assessed by immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Quantitative real-time PCR (qRT-PCR) and western blot analysis were performed to verify the expression levels of the candidate biomarkers. Patient disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier method. The prognostic biomarkers were identified by univariate analysis with a log-rank test and by multivariate analysis with Cox proportional hazards regression models. RESULTS:The GGH and FAAH protein levels were significantly up-regulated in invasive breast cancer tumors compared with adjacent non-cancerous tissues. Furthermore, the protein levels of GGH and FAAH were significantly correlated in tumor tissues. Tumoral GGH protein expression was significantly correlated with shorter DSS and RFS. Furthermore, the protein expression of GGH was positively correlated with undifferentiated tumors (BRE grade III) and ER/PR expressing tumors. Multivariate regression analysis showed that only GGH protein expression independently predicts DSS. No such correlations were found for FAAH, PIR and TAF5L protein expression. However, elevated protein levels of FAAH were positively associated with high number of lymph node involvement and upregulated levels of PIR were positively related with lymph node metastasis. The TAF5L was pronouncedly down-regulated in primary invasive breast cancer tissues compared to matched adjacent non-cancerous tissues. CONCLUSION:These data show for the first time that cytoplasmic GGH might play a relevant role in the development and progression of invasive breast cancer, warranting further investigations. Our findings suggest that GGH serve as a potential biomarker of unfavorable clinical outcomes over short-term follow-up in breast cancer. The GGH may be a very attractive targeted therapy for selected patients.

Project description:BackgroundThe active thyroid hormone triiodothyronine (T3) has been found to have an estrogen-like effect on breast cancer cells. Thyroid hormone receptor alpha-2 (THRα-2) acts as an antagonist for triiodothyronine (T3) signaling, and a low expression has been associated with unfavorable tumor characteristics and a higher mortality in breast cancer. However, the evidence are not conclusive. The present study evaluates tumor-specific THRα-2 expression in invasive breast cancers and its association with tumor characteristics and long-term mortality in a large population.MethodThe Malmö Diet and Cancer Study (MDCS), a population-based cohort in Sweden that included 17,035 women from 1991 to 1996, was used. Women diagnosed with breast cancer during 1991-2010 were eligible for inclusion. A tissue micro array was constructed from stored tumor material and stained for THRα-2 using immunohistochemistry. Tumors from 654 patients were scored regarding the intensity and the fraction of cells stained, then dichotomized into low or high expression. Date and cause of death were collected up until 2018-12-31. Tumor- and patient characteristics were available from the MDCS. Missing data was imputed using chained equations. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for low vs high expression of THRα-2 related to specific tumor factors. Mortality was evaluated with Kaplan-Meier curves and Cox regression, rendering hazard ratios (HRs). Analyses were also stratified for estrogen receptor (ER) status.ResultsWe found strong evidence of an association between low THRα-2 and unfavorable tumor characteristics, including estrogen receptor negativity: OR 4.04 (95% CI 2.28-7.15) and tumor size > 20-50 mm: OR 2.20 (95% CI 1.39-3.49). We found evidence of increased breast cancer-specific mortality for women with low THRα-2, HR 1.38 (95% CI 0.96-1.99), which remained after adjusting for age at diagnosis, HR 1.48 (95% CI 1.03-2.14), but not after adjusting for relevant prognostic factors, HR 0.98 (95% CI 0.66-1.45). THRα-2 expression in ER-negative tumors had an inverse correlation with overall mortality, HR 0.27 (95% CI 0.11-0.65).ConclusionLow tumor-specific THRα-2 expression was in this study associated with prognostically unfavorable tumor characteristics and a higher mortality in breast cancer, but not independent from other prognostic factors.

Project description:BackgroundKIF20A plays an indispensable role in cytokinesis regulation, which is important for tumor proliferation and growth. Recently, the oncogenic role of KIF20A has been well documented in several cancers. However, its clinical role in epithelial ovarian cancer (EOC) remains not reported yet. We investigated its expression and its role in promoting invasion and chemoresistance in EOC cells.Patients and methodsKIF20A transcription and translation levels were investigated in normal ovarian epithelial cell, ovarian cancer cells, and 10 pairs of fresh EOC tissues and adjacent normal ovarian tissues by real-time quantitative polymerase chain reaction and Western blots. Moreover, KIF20A protein level was also examined by immunohistochemistry in 150 EOC tissues. The correlation between KIF20A expression and clinical variables was analyzed by statistical methods. We also used wound healing assay, transwell assay MTT, and Annexin V/PI to explore KIF20A functions.ResultsKIF20A expression was obviously elevated at both mRNA and protein levels in EOC cell lines and clinical cancer tissues compared with normal ovarian epithelial cell and adjacent normal ovarian tissues. KIF20A protein expression was highly correlated with International Federation of Gynecology and Obstetrics stage (P=0.008), lymph node metastasis (P=0.002), intraperitoneal metastasis (P<0.001), vital status at last follow-up (P<0.001), intraperitoneal recurrence (P=0.030), tumor recurrence (P=0.005), drug resistance (P=0.013), and ascites with tumor cells (P<0.001). KIF20A overexpression was closely related to poorer overall survival and disease progression-free survival. Furthermore, Cox regression analysis revealed that KIF20A can act as an independent hazard indicator for predicting clinical outcomes in EOC patients. Interestingly, KIF20A overexpression promoted invasion and metastasis of EOC cells and also confers resistance to cisplatin.ConclusionOur findings indicated that KIF20A overexpression predicts unfavorable clinical outcome, revealing that KIF20A holds a promising potential to serve as a useful prognostic biomarker for EOC patients.

Project description:BackgroundThe oncogenic role of excision repair cross-complementation group 6-like (ERCC6L) has been revealed in several cancers recently, but little is known about its expression and function in hepatocellular carcinoma (HCC).MethodsUtilizing public data from Human Protein Atlas (HPA) and The Cancer Genome Atlas (TCGA) databases, ERCC6L dysregulation in HCC and its clinical significance were determined by t-test and Chi-square test. Comprehensive survival analyses (such as nomogram, Cox regression model and Kaplan-Meier analysis) were performed to assess prognostic value of ERCC6L for HCC patients. Integrated bioinformatics analyses [including copy number alterations (CNA), DNA methylation, miRNA prediction and gene set enrichment analysis (GSEA)] were conducted to explore the mechanisms and biological roles underlying ERCC6L dysregulation in HCC.ResultsERCC6L upregulation was identified in HCC tissues compared to normal controls (P<0.05). In addition, overexpression of ERCC6L not only correlated with elevated alpha fetoprotein (AFP), vascular invasion (VI), and advanced histologic grade and TNM stage, but also had an independent prognostic value for the poorer overall survival (OS) and recurrence-free survival (RFS) of HCC patients (all P<0.05). Besides, nomogram integrating ERCC6L expression and TNM stage showed superior prognostic ability than that of TNM stage (P<0.05). Moreover, ERCC6L promoter hypomethylation and miR-5589 downregulation in HCC might result in ERCC6L overexpression (all P<0.05). Furthermore, eight biological pathways (including the DNA replication, cell cycle and p53 pathways) related to ERCC6L upregulation in HCC were found to be enriched by GSEA, and ERCC6L upregulation was positively correlated with PLK1 (polo-like kinase 1) expression and TP53 mutation in HCC, which preliminarily shed light on the roles of ERCC6L in HCC.ConclusionsERCC6L may serve as a promising prognostic indicator and therapeutic target for HCC patients.

Project description:BackgroundChemokine (C-X-C motif) ligands (CXCLs) are important regulators of tumor progression in many cancers and could serve as potential cancer biomarkers. However, the expression patterns as well as functions of CXCLs remain unclear in penile cancer (PC). The aim of this study was to evaluate the usefulness of serum CXCL13 as a potential cancer biomarker for PC.Patients and methodsThis retrospective study enrolled 76 patients diagnosed with PC between 2016 and 2018. Serum CXCL13 level was detected by enzyme-linked immunosorbent assay. Univariable and multivariable Cox regression analyses were conducted to identify the prognostic factors that influence disease-free survival. Human penile cancer cell lines Penl1, Penl2, 149RCa and LM156 were used as in vitro models. The expression of CXCL13 protein in PC cell lines was analyzed by Western blotting.ResultsOur initial analysis on GSE57955 dataset identified CXCL13 as a top CXCL gene enriched in PC. Higher preoperative serum CXCL13 level was detected in PC cohorts than in healthy male controls (P<0.001). The area under the curve was 0.911 with the sensitivity of 84.2% and specificity of 87.0% to distinguish PC. Preoperative serum CXCL13 level was associated with pathological grade (P=0.048), T stage (P=0.009), nodal status (P<0.001) and pelvic lymph node metastasis (P=0.005) in PC. Serum CXCL13 level could serve as an independent prognostic factor for disease-free survival with a HR of 3.818 (95%CI: 1.126-12.946). Furthermore, autocrine expression of CXCL13 was detected in PC tissues and cell lines. Knockdown of CXCL13 expression suppressed malignant phenotypes (cell proliferation, clonogenesis, apoptosis escape, migration and invasion), attenuated STAT3 and ERK1/2 signaling and reduced MMP2/9 secretion in PC cell lines.ConclusionSerum CXCL13 could serve as a novel diagnostic and prognostic biomarker for PC. CXCL13 signaling might activate oncogenic signaling pathways to promote malignant progression of PC.

Dataset Information

Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes.

Publications

Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets