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miRNA expression profiling of 51 human breast cancer cell lines reveals subtype and driver mutation-specific miRNAs.

Riaz M, van Jaarsveld MT, Hollestelle A, Prager-van der Smissen WJ, Heine AA, Boersma AW, Liu J, Helmijr J, Ozturk B, Smid M, Wiemer EA, Foekens JA, Martens JW - Breast Cancer Res. (2013)

Bottom Line: Thirty miRNAs were associated with p16INK4 status while only a few miRNAs were associated with BRCA1, PIK3CA/PTEN and TP53 mutation status.Twelve miRNAs were associated with DNA copy number variation of the respective locus.Specific sets of miRNAs were associated with ERBB2 overexpression, p16INK4a or E-cadherin mutation or E-cadherin methylation status, which implies that these miRNAs may contribute to the driver role of these genetic aberrations.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Breast cancer is a genetically and phenotypically complex disease. To understand the role of miRNAs in this molecular complexity, we performed miRNA expression analysis in a cohort of molecularly well-characterized human breast cancer cell lines to identify miRNAs associated with the most common molecular subtypes and the most frequent genetic aberrations.

Methods: Using a microarray carrying LNA™ modified oligonucleotide capture probes), expression levels of 725 human miRNAs were measured in 51 breast cancer cell lines. Differential miRNA expression was explored by unsupervised cluster analysis and was then associated with the molecular subtypes and genetic aberrations commonly present in breast cancer.

Results: Unsupervised cluster analysis using the most variably expressed miRNAs divided the 51 breast cancer cell lines into a major and a minor cluster predominantly mirroring the luminal and basal intrinsic subdivision of breast cancer cell lines. One hundred and thirteen miRNAs were differentially expressed between these two main clusters. Forty miRNAs were differentially expressed between basal-like and normal-like/claudin-low cell lines. Within the luminal-group, 39 miRNAs were associated with ERBB2 overexpression and 24 with E-cadherin gene mutations, which are frequent in this subtype of breast cancer cell lines. In contrast, 31 miRNAs were associated with E-cadherin promoter hypermethylation, which, contrary to E-cadherin mutation, is exclusively observed in breast cancer cell lines that are not of luminal origin. Thirty miRNAs were associated with p16INK4 status while only a few miRNAs were associated with BRCA1, PIK3CA/PTEN and TP53 mutation status. Twelve miRNAs were associated with DNA copy number variation of the respective locus.

Conclusion: Luminal-basal and epithelial-mesenchymal associated miRNAs determine the subdivision of miRNA transcriptome of breast cancer cell lines. Specific sets of miRNAs were associated with ERBB2 overexpression, p16INK4a or E-cadherin mutation or E-cadherin methylation status, which implies that these miRNAs may contribute to the driver role of these genetic aberrations. Additionally, miRNAs, which are located in a genomic region showing recurrent genetic aberrations, may themselves play a driver role in breast carcinogenesis or contribute to a driver gene in their vicinity. In short, our study provides detailed molecular miRNA portraits of breast cancer cell lines, which can be exploited for functional studies of clinically important miRNAs.

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Differentially expressed miRNAs between p16INK4a mutant and wild-type cell lines in the estrogen receptor-negative/basal-group. The analysis was restricted to only the estrogen receptor (ER)-negative/basal-group of cell lines since the majority of p16INK4a mutant cell lines were ER-negative. Yellow and blue, high and low overall similarity of samples in miRNA expression, respectively.
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Figure 5: Differentially expressed miRNAs between p16INK4a mutant and wild-type cell lines in the estrogen receptor-negative/basal-group. The analysis was restricted to only the estrogen receptor (ER)-negative/basal-group of cell lines since the majority of p16INK4a mutant cell lines were ER-negative. Yellow and blue, high and low overall similarity of samples in miRNA expression, respectively.

Mentions: In our cohort, 13 cell lines had lost the p16INK4a locus, of which the majority are ER-negative. The comparison revealed that 30 miRNAs were differentially expressed between nine p16INK4a mutant cell lines and seven wild-type cell lines in the ER-negative/basal-group (Figure 5; see Table S12 in Additional file 1). The most highly expressed miRNAs in p16INK4a mutant cell lines were hsa-miR-29a and hsa-miR-100 (fold change ≥ 2). Notably, the p16INK4a miRNA signature in the ER-negative/basal-group of cell lines appeared to be pronounced, and when used for clustering could almost completely separate the cell lines mutant for the p16INK4agene from those that were wild-type. One should, however, emphasize that the tumor suppressor genes p16INK4a and p14ARF are co-localized and are often simultaneously lost amongst cell lines. We therefore cannot determine which of these genes might drive the differential expression of these miRNAs.


miRNA expression profiling of 51 human breast cancer cell lines reveals subtype and driver mutation-specific miRNAs.

Riaz M, van Jaarsveld MT, Hollestelle A, Prager-van der Smissen WJ, Heine AA, Boersma AW, Liu J, Helmijr J, Ozturk B, Smid M, Wiemer EA, Foekens JA, Martens JW - Breast Cancer Res. (2013)

Differentially expressed miRNAs between p16INK4a mutant and wild-type cell lines in the estrogen receptor-negative/basal-group. The analysis was restricted to only the estrogen receptor (ER)-negative/basal-group of cell lines since the majority of p16INK4a mutant cell lines were ER-negative. Yellow and blue, high and low overall similarity of samples in miRNA expression, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672661&req=5

Figure 5: Differentially expressed miRNAs between p16INK4a mutant and wild-type cell lines in the estrogen receptor-negative/basal-group. The analysis was restricted to only the estrogen receptor (ER)-negative/basal-group of cell lines since the majority of p16INK4a mutant cell lines were ER-negative. Yellow and blue, high and low overall similarity of samples in miRNA expression, respectively.
Mentions: In our cohort, 13 cell lines had lost the p16INK4a locus, of which the majority are ER-negative. The comparison revealed that 30 miRNAs were differentially expressed between nine p16INK4a mutant cell lines and seven wild-type cell lines in the ER-negative/basal-group (Figure 5; see Table S12 in Additional file 1). The most highly expressed miRNAs in p16INK4a mutant cell lines were hsa-miR-29a and hsa-miR-100 (fold change ≥ 2). Notably, the p16INK4a miRNA signature in the ER-negative/basal-group of cell lines appeared to be pronounced, and when used for clustering could almost completely separate the cell lines mutant for the p16INK4agene from those that were wild-type. One should, however, emphasize that the tumor suppressor genes p16INK4a and p14ARF are co-localized and are often simultaneously lost amongst cell lines. We therefore cannot determine which of these genes might drive the differential expression of these miRNAs.

Bottom Line: Thirty miRNAs were associated with p16INK4 status while only a few miRNAs were associated with BRCA1, PIK3CA/PTEN and TP53 mutation status.Twelve miRNAs were associated with DNA copy number variation of the respective locus.Specific sets of miRNAs were associated with ERBB2 overexpression, p16INK4a or E-cadherin mutation or E-cadherin methylation status, which implies that these miRNAs may contribute to the driver role of these genetic aberrations.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Breast cancer is a genetically and phenotypically complex disease. To understand the role of miRNAs in this molecular complexity, we performed miRNA expression analysis in a cohort of molecularly well-characterized human breast cancer cell lines to identify miRNAs associated with the most common molecular subtypes and the most frequent genetic aberrations.

Methods: Using a microarray carrying LNA™ modified oligonucleotide capture probes), expression levels of 725 human miRNAs were measured in 51 breast cancer cell lines. Differential miRNA expression was explored by unsupervised cluster analysis and was then associated with the molecular subtypes and genetic aberrations commonly present in breast cancer.

Results: Unsupervised cluster analysis using the most variably expressed miRNAs divided the 51 breast cancer cell lines into a major and a minor cluster predominantly mirroring the luminal and basal intrinsic subdivision of breast cancer cell lines. One hundred and thirteen miRNAs were differentially expressed between these two main clusters. Forty miRNAs were differentially expressed between basal-like and normal-like/claudin-low cell lines. Within the luminal-group, 39 miRNAs were associated with ERBB2 overexpression and 24 with E-cadherin gene mutations, which are frequent in this subtype of breast cancer cell lines. In contrast, 31 miRNAs were associated with E-cadherin promoter hypermethylation, which, contrary to E-cadherin mutation, is exclusively observed in breast cancer cell lines that are not of luminal origin. Thirty miRNAs were associated with p16INK4 status while only a few miRNAs were associated with BRCA1, PIK3CA/PTEN and TP53 mutation status. Twelve miRNAs were associated with DNA copy number variation of the respective locus.

Conclusion: Luminal-basal and epithelial-mesenchymal associated miRNAs determine the subdivision of miRNA transcriptome of breast cancer cell lines. Specific sets of miRNAs were associated with ERBB2 overexpression, p16INK4a or E-cadherin mutation or E-cadherin methylation status, which implies that these miRNAs may contribute to the driver role of these genetic aberrations. Additionally, miRNAs, which are located in a genomic region showing recurrent genetic aberrations, may themselves play a driver role in breast carcinogenesis or contribute to a driver gene in their vicinity. In short, our study provides detailed molecular miRNA portraits of breast cancer cell lines, which can be exploited for functional studies of clinically important miRNAs.

Show MeSH
Related in: MedlinePlus