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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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Molecular subtype-specific differential expression of miRNAs. Differentially expressed miRNAs (A) between luminal-type and luminal ERBB2-positive breast cancer cell lines within the mRNA-derived luminal-group (see Figure 1), and (B) between basal-like and normal-like/claudin-low breast cancer cell lines within the mRNA-derived estrogen receptor-negative/basal-group. Yellow and blue, high and low overall similarity of samples in miRNA expression, respectively.
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Figure 3: Molecular subtype-specific differential expression of miRNAs. Differentially expressed miRNAs (A) between luminal-type and luminal ERBB2-positive breast cancer cell lines within the mRNA-derived luminal-group (see Figure 1), and (B) between basal-like and normal-like/claudin-low breast cancer cell lines within the mRNA-derived estrogen receptor-negative/basal-group. Yellow and blue, high and low overall similarity of samples in miRNA expression, respectively.

Mentions: We next aimed to identify miRNAs that are differentially expressed between the intrinsic subtypes of breast cancer. As expected, we observed a substantial overlap of differentially expressed miRNAs between ER-positive and ER-negative cell lines and the luminal-group and ER-negative/basal-group of cell lines (see Figure S1 in Additional file 2 and Tables S4A and S7 in Additional file 1). To identify additional miRNAs that are related to intrinsic subtypes but to avoid the confounding effect of ER, we compared cell lines with and without ERBB2 overexpression within the luminal-group. Likewise we compared the intrinsic basal-like cell lines with normal-like/claudin-low cell lines within the ER-negative/basal-group. These comparisons revealed 39 differentially expressed miRNAs in luminal cell lines with or without overexpressed ERBB2; 40 miRNAs were found differentially expressed between basal-like and normal-like/claudin-low cell lines (P < 0.05) (Figure 3A, B; see Tables S8 and S9 in Additional file 1).


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)

Molecular subtype-specific differential expression of miRNAs. Differentially expressed miRNAs (A) between luminal-type and luminal ERBB2-positive breast cancer cell lines within the mRNA-derived luminal-group (see Figure 1), and (B) between basal-like and normal-like/claudin-low breast cancer cell lines within the mRNA-derived estrogen receptor-negative/basal-group. 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 3: Molecular subtype-specific differential expression of miRNAs. Differentially expressed miRNAs (A) between luminal-type and luminal ERBB2-positive breast cancer cell lines within the mRNA-derived luminal-group (see Figure 1), and (B) between basal-like and normal-like/claudin-low breast cancer cell lines within the mRNA-derived estrogen receptor-negative/basal-group. Yellow and blue, high and low overall similarity of samples in miRNA expression, respectively.
Mentions: We next aimed to identify miRNAs that are differentially expressed between the intrinsic subtypes of breast cancer. As expected, we observed a substantial overlap of differentially expressed miRNAs between ER-positive and ER-negative cell lines and the luminal-group and ER-negative/basal-group of cell lines (see Figure S1 in Additional file 2 and Tables S4A and S7 in Additional file 1). To identify additional miRNAs that are related to intrinsic subtypes but to avoid the confounding effect of ER, we compared cell lines with and without ERBB2 overexpression within the luminal-group. Likewise we compared the intrinsic basal-like cell lines with normal-like/claudin-low cell lines within the ER-negative/basal-group. These comparisons revealed 39 differentially expressed miRNAs in luminal cell lines with or without overexpressed ERBB2; 40 miRNAs were found differentially expressed between basal-like and normal-like/claudin-low cell lines (P < 0.05) (Figure 3A, B; see Tables S8 and S9 in Additional file 1).

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