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

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 p16(INK4 )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, p16(INK4a )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

The transcription factors Emx1 and Emx2 suppress choroid plexus development and promote neuroepithelial cell fate.

The transcription factors Emx1 and Emx2 exert important functions during development of the cerebral cortex, including its arealization. Here, we addressed their role in development of the derivatives of the midline region in the telencephalon. The center of the midline region differentiates into the choroid plexus, but little is known about its molecular specification. As we noted a lack of Emx1 or 2 expression in the midline region early in development, we interfered by misexpressing Emx1 and/or Emx2 in this region of the chick telencephalon. Ectopic expression of either Emx1 or Emx2 prior to HH 13 instructed a neuroepithelial identity in the previous midline region instead of a choroidal fate. Thus, Gli3 and Lhx2 normally restricted to the neuroepithelium expanded into the Emx misexpressing region. This was accompanied by down-regulation of Otx2 and BMP7, which implicates that these factors are essential for choroid plexus specification and differentiation. Interestingly, the region next to the ectopic Emx-misexpression then acquired a hybrid identity with some choroidal features such as Bmp7, Otx2 and Ttr gene expression, as well as some neuroepithelial features. These observations indicate that the expression levels of Emx1 and/or Emx2 restrict the prospective choroid plexus territory, a novel role of these transcription factors

Expression of Ngn1, Ngn2, Cash1, Gsh2 and Sfrp1 in the developing chick telencephalon

Patterning of the chick telencephalon has been debated, especially in regard to a ventral (subpallial) or dorsal (pallial) nature of the dorsal ventricular ridge (DVR). Here we report the expression patterns of chick homologues of molecules known to be involved in telencephalic patterning in other vertebrate species, We show here that the transcription factors Ngn1, Ngn2, Cash1, Gsh2 and the secreted frizzled related protein 1 (sfrp1), a wnt receptor, arc expressed in characteristic telencephalic domains during chick development. At embryonic day 7 (E7) Ngn1 and Ngn2 are localized in the dorsal pallium and the DVR, similar to the region of Pax6 expression. In contrast, Gsh2 and Cash1 are restricted to the subpallium and some DVR cells. Interestingly Sfrp, a dorsoventral boundary marker in mouse telencephalon, is expressed between the DVR and subpallium. Gsh2 and Pax6 double- positive cells further characterize this boundary region in the developing chick telencephalon. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved