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Proteomic Analysis of Urine to Identify Breast Cancer Biomarker Candidates Using a Label-Free LC-MS/MS Approach.

ABSTRACT: Breast cancer is a complex heterogeneous disease and is a leading cause of death in women. Early diagnosis and monitoring progression of breast cancer are important for improving prognosis. The aim of this study was to identify protein biomarkers in urine for early screening detection and monitoring invasive breast cancer progression.We performed a comparative proteomic analysis using ion count relative quantification label free LC-MS/MS analysis of urine from breast cancer patients (n = 20) and healthy control women (n = 20).Unbiased label free LC-MS/MS-based proteomics was used to provide a profile of abundant proteins in the biological system of breast cancer patients. Data analysis revealed 59 urinary proteins that were significantly different in breast cancer patients compared to the normal control subjects (p<0.05, fold change >3). Thirty-six urinary proteins were exclusively found in specific breast cancer stages, with 24 increasing and 12 decreasing in their abundance. Amongst the 59 significant urinary proteins identified, a list of 13 novel up-regulated proteins were revealed that may be used to detect breast cancer. These include stage specific markers associated with pre-invasive breast cancer in the ductal carcinoma in-situ (DCIS) samples (Leucine LRC36, MAST4 and Uncharacterized protein CI131), early invasive breast cancer (DYH8, HBA, PEPA, uncharacterized protein C4orf14 (CD014), filaggrin and MMRN2) and metastatic breast cancer (AGRIN, NEGR1, FIBA and Keratin KIC10). Preliminary validation of 3 potential markers (ECM1, MAST4 and filaggrin) identified was performed in breast cancer cell lines by Western blotting. One potential marker MAST4 was further validated in human breast cancer tissues as well as individual human breast cancer urine samples with immunohistochemistry and Western blotting, respectively.Our results indicate that urine is a useful non-invasive source of biomarkers and the profile patterns (biomarkers) identified, have potential for clinical use in the detection of BC. Validation with a larger independent cohort of patients is required in the following study.

SUBMITTER: Beretov J

PROVIDER: S-EPMC4636393 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Proteomic Analysis of Urine to Identify Breast Cancer Biomarker Candidates Using a Label-Free LC-MS/MS Approach.

Beretov Julia J Wasinger Valerie C VC Millar Ewan K A EK Schwartz Peter P Graham Peter H PH Li Yong Y

PloS one 20151106 11

<h4>Introduction</h4>Breast cancer is a complex heterogeneous disease and is a leading cause of death in women. Early diagnosis and monitoring progression of breast cancer are important for improving prognosis. The aim of this study was to identify protein biomarkers in urine for early screening detection and monitoring invasive breast cancer progression.<h4>Method</h4>We performed a comparative proteomic analysis using ion count relative quantification label free LC-MS/MS analysis of urine from ...[more]

PMID: 26544852

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Project description:IntroductionBladder cancer (BC) is a significant carcinoma of the urinary system that has a high incidence of morbidity and death owing to the challenges in accurately identifying people with early-stage BC and the lack of effective treatment options for those with advanced BC. Thus, there is a need to define new markers of prognosis and prediction.MethodsIn this study, we have performed a comprehensive proteomics experiment by label-free quantitative proteomics to compare the proteome changes in the serum of normal people and bladder cancer patients-the successful quantification of 2064 Quantifiable proteins in total. A quantitative analysis was conducted to determine the extent of changes in protein species' relative intensity and reproducibility. There were 43 upregulated proteins and 36 downregulated proteins discovered in non-muscle invasive bladder cancer and normal individuals. Sixty-four of these proteins were elevated, and 51 were downregulated in muscle-invasive and non-muscle-invasive bladder cancer, respectively. Functional roles of differentially expressed proteins were annotated using Gene Ontology (GO) and Clusters of Orthologous Groups of Proteins (COG). To analyze the functions and pathways enriched by differentially expressed proteins, GO enrichment analysis, protein domain analysis, and KEGG pathway analysis were performed. The proteome differences were examined and visualized using radar plots, heat maps, bubble plots, and Venn diagrams.ResultsAs a result of combining the Venn diagram with protein-protein interactions (PPIs), Chloride intracellular channel 1 (CLIC1) was identified as the primary protein. Using the Gene Set Cancer Analysis (GSCA) website, the influence of CLIC1 on immune infiltration was analyzed. A negative correlation between CD8 naive and CLIC1 levels was found. For validation, immunohistochemical (IHC), qPCR, and western blotting (WB) were performed.Further, we found that CLIC1 was associated with a poor prognosis of bladder cancer in survival analysis.DiscussionOur research screened CLIC1 as a tumor-promoting protein in bladder cancer for the first time using serum mass spectrometry. And CLIC1 associated with tumor stage, and immune infiltrate. The prognostic biomarker and therapeutic target CLIC1 may be new for bladder cancer patients.

Dataset Information

Proteomic Analysis of Urine to Identify Breast Cancer Biomarker Candidates Using a Label-Free LC-MS/MS Approach.

Publications

Proteomic Analysis of Urine to Identify Breast Cancer Biomarker Candidates Using a Label-Free LC-MS/MS Approach.

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