Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Molecular Characterization of Breast Cancer Subtypes from Joint Analysis of High Throughput miRNA and mRNA Data (II)

ABSTRACT: MicroRNAs (miRNAs) are a class of short, single-stranded widely expressed noncoding RNAs that regulate the stability or translational efficiency of target messenger RNAs. Date derived from expression profiling of 489 miRNAs in 101 human primary breast tumor samples, along with genome-wide matched mRNA profiling and extensive clinical information were investigated in this study. miRNA and mRNA expression were analyzed using correlations and enrichments analyses. The results show that particular cellular processes such as proliferation, cell adhesion, and immune response are significantly enriched among genes with strong positive or negative correlation to individual or groups of miRNAs. Functional analyses were performed to validate the influence of miRNAs on proliferation. A group of miRNAs was identified that is associated to breast cancer disease free survival. This study provides a comprehensive dataset that can be used as groundwork for further studies of the involvement of miRNA in breast cancer. miRNA profiling from 101 breast cancer samples was performed. Experiments were mostly performed using duplicate hybridizations (99 samples) on different arrays and time points. Two samples were profiled only once. miRNA signal intensities for replicate probes were averaged across the platform, log2 transformed and normalized to the 75 percentile. miRNA expression status was scored as present or absent for each gene in each sample by default settings in FE v9.5. miRNAs in samples that were run in replicates were considered present if scored in one of the two arrays. mRNA profiling from 115 breast cancer samples was performed. Replicates not included. Four new arrays were added in this version with 115 samples versus the one with 114 samples (GSE19536). For samples 34, 107 and 185, a new array replaces the old one, generally with only small differences in values. Sample 391 is added to the 115 sample dataset. Replicates not included.

ORGANISM(S): Homo sapiens

SUBMITTER: Hilde Johnsen

PROVIDER: E-GEOD-19783 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: The global effect of copy number and epigenetic alterations on miRNA expression in cancer is poorly understood. In the present study, we integrate genome-wide copy number, DNA methylation and miRNA expression and identify genetic mechanisms underlying miRNA dysregulation in breast cancer. Results: We identify 70 miRNAs whose expression was associated with aberrations in copy number or methylation, or both. Among these, five miRNA families are represented. Interestingly, the members of these families are encoded on different chromosomes and are complementarily altered by gain or hypomethylation across the patients. In an independent breast cancer cohort of 123 patients, 41 of the 70 miRNAs were confirmed with respect to aberration pattern and association to expression. In vitro functional experiments were performed in breast cancer cell lines with miRNA mimics to evaluate the phenotype of the replicated miRNAs. let-7e-3p, which in tumors is found associated with hypermethylation, is shown to induce apoptosis and reduce cell viability, and low let-7e-3p expression is associated with poorer prognosis. The overexpression of three other miRNAs associated with copy number gain, miR-21-3p, miR-148b-3p and miR-151a-5p, increases proliferation of breast cancer cell lines. In addition, miR-151a-5p enhances the levels of phosphorylated AKT protein. Conclusions: Our data provide novel evidence of the mechanisms behind miRNA dysregulation in breast cancer. The study contributes to the understanding of how methylation and copy number aberrations influence miRNA expression, emphasizing miRNA functionality through redundant encoding, and suggests novel miRNAs important in breast cancer. The miRNA expression profiling of 149 breast cancer samples was performed using the 8x15k “Human miRNA Microarray Kit (V2)” with design id 019118 from Agilent (Agilent Technologies, Santa Clara, CA, USA). In brief, 100 ng total RNA was dephosphorylated, labeled and hybridized for 20 hours, following the manufacturer’s protocol. Scanning was performed on Agilent Scanner G2565A, signals were extracted using Feature Extraction v9.5 and the subsequent data processing was performed using the GeneSpring software v12.0 (Agilent Technologies). In brief, the miRNA signal intensities were log2-transformed and normalized to the 90th percentile, and miRNAs that were detected in less than 10% of the samples were excluded. This resulted in 448 unique mature miRNAs.

Project description:Transcription signatures have been used to stratify breast cancer patients into clinically distinct subgroups. However, transcription alone does not determine protein expression. Of potentially equal importance for determining the tumor phenotype is the rate at which transcripts are translated to form protein. Protein translation is controlled to a major degree by miRNA, and cancer cells may deregulate the expression of key genes by altering the activity of relevant miRNAs. The importance of miRNA deregulation and the extent to which multiple miRNAs coordinately deregulate key proteins in breast cancer is only partly understood. To gain such insight, we analyzed genome-wide miRNA expression and mRNA/protein expression for a panel of 105 selected cancer related genes in breast carcinomas from 283 patients. The miRNA-mRNA-protein interactome for the selected genes was constructed by modeling protein expression as a joint function of mRNA and miRNA expression, considering the effect of both one miRNA at a time, and all studied miRNAs simultaneously. The interactome represents a map of the global effects of miRNAs on protein expression, capturing direct as well as indirect effects. The results reveal extensive association between miRNA and protein expression as well as coordinated effects of multiple miRNAs on individual proteins. Applying the model onto two other independent primary breast cancer cohorts confirmed the generalizability of key aspects of the interactome map. The miRNA expression profiling of 283 breast cancer samples was performed using the 8x15k “Human miRNA Microarray Kit release 14.0 (V2)” with design id 029297 from Agilent (Agilent Technologies, Santa Clara, CA, USA). In brief, 100 ng total RNA was dephosphorylated, labeled and hybridized for 20 hours, following the manufacturer’s protocol. Scanning was performed on Agilent Scanner G2565A, signals were extracted using Feature Extraction v10.7.3.1 and the subsequent data processing was performed using the GeneSpring software v11.0 (Agilent Technologies). In brief, the miRNA signal intensities were log2-transformed and normalized to the 90th percentile, and miRNAs that were detected in less than 10% of the samples were excluded. This resulted in 421 unique mature miRNAs. The Oslo Breast Cancer Consortium (OSBREAC)

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Molecular Characterization of Breast Cancer Subtypes from Joint Analysis of High Throughput miRNA and mRNA Data (II)

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