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GSE7390
Homo sapiens
197 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
Background: Recently a 76-gene prognostic signature able to predict distant metastases in lymph node-negative (N-) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment. Materials and Methods: Gene expression profiling of frozen samples from 198 N- systemically untreated patients was performed at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were performed with the genomic risk and adjusted for the clinical risk, defined by Adjuvant!Online. Results: The actual 5- and 10-year time to distant metastasis (TDM) were 98% (88%-100%) and 94% (83%-98%) respectively for the good profile group and 76% (68%- 82%) and 73% (65%-79%) for the poor profile group. The actual 5- and 10-year overall survival (OS) were 98% (88%-100%) and 87% (73%-94%) respectively for the good profile group and 84% (77%-89%) and 72% (63%-78%) for the poor profile group. We observed a strong time-dependency of this signature, leading to an adjusted HR of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years, and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for TDM and OS respectively. Conclusion: This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases.
Publication Title
Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series.
Sample Metadata Fields
Age, Disease stage
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Progesterone and estrogen are important drivers of breast cancer proliferation. Herein, we probed estrogen receptor- (ER) and progesterone receptor (PR) cross-talk in breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to estradiol and insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of estradiol-responsive ER target genes, including cathepsin-D (CTSD). Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the proline-, glutamate- and leucine-rich protein 1 (PELP1) to an estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human breast cancer samples. Inhibition of IGF1R or phosphoinositide 3-kinase blocked PR-B-dependent CTSD mRNA upregulation in response to estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or onapristone treatment of multiple unmodified breast cancer cell lines blocked estradiol-mediated CTSD induction, inhibited growth in soft agar and partially restored tamoxifen sensitivity of resistant cells. Further, combination treatment of breast cancer cells with both onapristone and IGF1R tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to estradiol and IGF1 via scaffolding of ER-/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with luminal breast cancer.
Publication Title
Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes.
Sample Metadata Fields
Treatment, Time
View Samples- Homo sapiens
- 78 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples, to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocytes and pDC specific, miR-150; lymphoid cells specific, miR-652 and miR-223; both myeloid cells specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA-mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA-mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p < 9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity.
Publication Title
Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 45 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples, to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocytes and pDC specific, miR-150; lymphoid cells specific, miR-652 and miR-223; both myeloid cells specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA-mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA-mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p < 9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity.
Publication Title
Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 33 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples, to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocytes and pDC specific, miR-150; lymphoid cells specific, miR-652 and miR-223; both myeloid cells specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA-mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA-mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p < 9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity.
Publication Title
Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Following androgen ablation therapy (AAT), the vast majority of prostate cancer patients develop treatment resistance with a median time of 18-24 months to disease progression. To identify molecular targets that aid in prostate cancer cell survival and contribute to the androgen independent phenotype, we evaluated changes in LNCaP cell gene expression during 12 months of androgen deprivation. At time points reflecting critical growth and phenotypic changes, we performed Affymetrix expression array analysis to examine the effects of androgen deprivation during the acute response, during the period of apparent quiescence, and during the emergence of highly proliferative, androgen-independent prostate cancer cells (LNCaP-AI). We discovered alterations in gene expression for a host of molecules associated with promoting prostate cancer cell growth and survival, regulating cell cycle progression, apoptosis and adrenal androgen metabolism, in addition to AR co-regulators and markers of neuroendocrine disease. These findings illustrate the complexity and unpredictable nature of cancer cell biology and contribute greatly to our understanding of how prostate cancer cells likely survive AAT. The value of this longitudinal approach lies in the ability to examine gene expression changes throughout the cellular response to androgen deprivation; it provides a more dynamic illustration of those genes which contribute to disease progression in addition to specific genes which constitute a malignant androgen-independent phenotype. In conclusion, it is of great importance that we employ new approaches, such as the one proposed here, to continue exploring the cellular mechanisms of therapy resistance and identify promising targets to improve cancer therapeutics.
Publication Title
Longitudinal analysis of androgen deprivation of prostate cancer cells identifies pathways to androgen independence.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 2 Downloadable Samples
Illumina Genome Analyzer II
Description
miRNAs are small non-coding RNAs that inhibit translation and promote mRNA decay. The levels of mature miRNAs are the result of different rates of transcription, processing, and turnover. The non-canonical polymerase Gld2 has been implicated in the stabilization of miR-122 possibly by catalyzing 3’ monoadenylation, however, there is little evidence that this relationship is one of cause and effect. Here, we biochemically characterize Gld2 involvement in miRNA monoadenylation and its effect on miRNA stability. We find that Gld2 directly monoadenylates and stabilizes specific miRNA populations in human fibroblasts and that sensitivity to monoadenylation-induced stability depends on nucleotides in the miRNA 3‘ end. These results establish a novel mechanism of miRNA stability and resulting post-transcriptional gene regulation. Overall design: Sequencing of miRNAs to assess amount and 3'' end monoadenylation state upon Gld2 knock-down.
Publication Title
Specific miRNA stabilization by Gld2-catalyzed monoadenylation.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 30 Downloadable Samples
- Illumina HumanHT-12 V3.0 expression beadchip
Description
INTRODUCTION. Fixation with formalin, a widely adopted procedure to preserve tissue samples, leads to extensive degradation of nucleic acids and thereby compromises procedures like microarray-based gene expression profiling. We hypothesized that RNA fragmentation is caused by activation of RNAses during the interval between formalin penetration and tissue fixation. To prevent RNAse activation, a series of tissue samples were kept under-vacuum at 4C until fixation and then fixed at 4C, for 24 hours, in formalin followed by 4 hours in ethanol 95%.
Publication Title
Formalin fixation at low temperature better preserves nucleic acid integrity.
Sample Metadata Fields
Specimen part
View Samples- Drosophila melanogaster
- 2 Downloadable Samples
- Illumina Genome Analyzer II
Description
Adult stem cells support tissue homeostasis and repair throughout the life of an individual. However, numerous intrinsic and extrinsic changes occur with age that result in altered stem cell behavior and reduced tissue maintenance and regeneration. In the Drosophila testis, stem cells surround and contact the apical hub, a cluster of somatic cells that express the self-renewal factor Unpaired (Upd), which activates the JAK-STAT pathway in adjacent stem cells. However, aging results in a dramatic decrease in upd expression, with a concomitant loss of germline stem cells (GSCs). Here we present genetic and biochemical data to demonstrate that IGF-II mRNA binding protein (Imp) counteracts endogenous small interfering RNAs to stabilize upd RNA and contribute to maintenance of the niche. However, Imp expression decreases in hub cells of older males, similar to upd, which is due to targeting of Imp by the heterochronic microRNA let-7. Therefore, in the absence of Imp, upd mRNA becomes unprotected and susceptible to degradation. Understanding the mechanistic basis for aging-related changes in stem cell behavior will lead to the development of strategies to treat age-onset diseases and facilitate stem cell based therapies in older individuals. Overall design: Examination of small RNA levels in testes from young (1day old) and aged (30days old) males of Drosophila melanogaster by deep sequencing (using Illumina GAII).
Publication Title
The let-7-Imp axis regulates ageing of the Drosophila testis stem-cell niche.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 14 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Using a hitherto uncharacterized knockout mouse model of Notch 3, a Notch signaling receptor paralogue highly expressed in vascular SMCs, we uncover a striking susceptibility to ischemic stroke upon challenge. Cellular and molecular analyses of vascular SMCs derived from these animals associate Notch 3 activity to the expression of specific gene targets, whereas genetic rescue experiments unambiguously link Notch 3 function in vessels to the ischemic phenotype.
Publication Title
Notch signaling functions in retinal pericyte survival.
Sample Metadata Fields
Sex, Specimen part
View Samples