Article

Integrated miRNA and mRNA expression profiling of the inflammatory breast cancer subtype

Translational Cancer Research Group (Laboratory of Pathology, University of Antwerp/University Hospital Antwerp, Oncology Centre, Sint-Augustinus), Oosterveldlaan 24, B-2610 Antwerp, Belgium.
British Journal of Cancer (Impact Factor: 4.82). 08/2010; 103(4):532-41. DOI: 10.1038/sj.bjc.6605787
Source: PubMed

ABSTRACT MicroRNAs (miRNAs) are key regulators of gene expression. In this study, we explored whether altered miRNA expression has a prominent role in defining the inflammatory breast cancer (IBC) phenotype.
We used quantitative PCR technology to evaluate the expression of 384 miRNAs in 20 IBC and 50 non-IBC samples. To gain understanding on the biological functions deregulated by aberrant miRNA expression, we looked for direct miRNA targets by performing pair-wise correlation coefficient analysis on expression levels of 10 962 messenger RNAs (mRNAs) and by comparing these results with predicted miRNA targets from TargetScan5.1.
We identified 13 miRNAs for which expression levels were able to correctly predict the nature of the sample analysed (IBC vs non-IBC). For these miRNAs, we detected a total of 17,295 correlated miRNA-mRNA pairs, of which 7012 and 10 283 pairs showed negative and positive correlations, respectively. For four miRNAs (miR-29a, miR-30b, miR-342-3p and miR-520a-5p), correlated genes were concordant with predicted targets. A gene set enrichment analysis on these genes demonstrated significant enrichment in biological processes related to cell proliferation and signal transduction.
This study represents, to the best of our knowledge, the first integrated analysis of miRNA and mRNA expression in IBC. We identified a set of 13 miRNAs of which expression differed between IBC and non-IBC, making these miRNAs candidate markers for the IBC subtype.

Download full-text

Full-text

Available from: Peter van Dam, Aug 23, 2015
1 Follower
 · 
264 Views
  • Source
    • "This is consistent with published data describing global downregulation of miRNA expression in cancers (Gaur et al., 2007; Lu et al., 2005). Differential expression of the endogenous miRNA processing machinery represents a potential explanation for the repressive patterns of miRNA expression that we observed, as recent reports have highlighted the importance of miRNA processing genes in the regulation of miRNA biogenesis and function (Cheng et al., 2009; Van der Auwera et al., 2010). We examined the expression of dicer, Table 2. Effect of b4 expression on miRNA families. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The integrin α6β4 is defined as an adhesion receptor for laminins. Referred to as 'β4', this integrin plays a key role in the progression of various carcinomas through its ability to orchestrate key signal transduction events and promote cell motility. To identify novel downstream effectors of β4 function in breast cancer, microRNAs (miRNAs) were examined because of their extensive links to tumorigenesis and their ability to regulate gene expression globally. Two breast carcinoma cell lines and a collection of invasive breast carcinomas with varying β4 expression were used to assess the effect of this integrin on miRNA expression. A novel miRNA microarray analysis termed quantitative Nuclease Protection Assay (qNPA) revealed that β4 expression can significantly alter miRNA expression and identified two miRNA families, miR-25/32/92abc/363/363-3p/367 and miR-99ab/100, that are consistently downregulated by expression of this integrin. Analysis of published Affymetrix GeneChip data identified 54 common targets of miR-92ab and miR-99ab/100 within the subset of β4-regulated mRNAs, revealing several genes known to be key components of β4-regulated signaling cascades and effectors of cell motility. Gene ontology classification identified an enrichment in genes associated with cell migration within this population. Finally, gene set enrichment analysis of all β4-regulated mRNAs revealed an enrichment in targets belonging to distinct miRNA families, including miR-92ab and others identified by our initial array analyses. The results obtained in this study provide the first example of an integrin globally impacting miRNA expression and provide evidence that select miRNA families collectively target genes important in executing β4-mediated cell motility.
    Biology Open 07/2012; 1(7):658-66. DOI:10.1242/bio.20121628 · 2.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mammography is a powerful screening tool for early detection of breast cancer, but it has limitations in terms of both specificity and sensitivity. Imaging tools such as MRI that complement mammography are too costly to serve as first-line screens. Recently, progress has been made on blood markers, particularly microRNAs and proteins. There are new methods for protein marker discovery directly in blood, but they are limited in the number of patients that can be examined. An alternative is to discover markers as transcripts in tissues, followed by development of blood protein tests for those that perform best. To identify genes that are overexpressed in malignancy it is paramount to include normal control tissues from healthy individuals. Here we report the identification of potential breast cancer markers, including some that are overexpressed in aggressive disease.
    Annals of the New York Academy of Sciences 10/2010; 1210(1):78-85. DOI:10.1111/j.1749-6632.2010.05803.x · 4.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammatory breast cancer (IBC) is an aggressive form of BC poorly defined at the molecular level. We compared the molecular portraits of 63 IBC and 134 non-IBC (nIBC) clinical samples. Genomic imbalances of 49 IBCs and 124 nIBCs were determined using high-resolution array-comparative genomic hybridization, and mRNA expression profiles of 197 samples using whole-genome microarrays. Genomic profiles of IBCs were as heterogeneous as those of nIBCs, and globally relatively close. However, IBCs showed more frequent "complex" patterns and a higher percentage of genes with CNAs per sample. The number of altered regions was similar in both types, although some regions were altered more frequently and/or with higher amplitude in IBCs. Many genes were similarly altered in both types; however, more genes displayed recurrent amplifications in IBCs. The percentage of genes whose mRNA expression correlated with CNAs was similar in both types for the gained genes, but ∼7-fold lower in IBCs for the lost genes. Integrated analysis identified 24 potential candidate IBC-specific genes. Their combined expression accurately distinguished IBCs and nIBCS in an independent validation set, and retained an independent prognostic value in a series of 1,781 nIBCs, reinforcing the hypothesis for a link with IBC aggressiveness. Consistent with the hyperproliferative and invasive phenotype of IBC these genes are notably involved in protein translation, cell cycle, RNA processing and transcription, metabolism, and cell migration. Our results suggest a higher genomic instability of IBC. We established the first repertory of DNA copy number alterations in this tumor, and provided a list of genes that may contribute to its aggressiveness and represent novel therapeutic targets.
    PLoS ONE 02/2011; 6(2):e16950. DOI:10.1371/journal.pone.0016950 · 3.53 Impact Factor
Show more