Mir-30e* is an independent subtype-specific prognostic marker in breast cancer
ABSTRACT: Both gene and miRNA expression patterns separately correlate with survival in breast cancer suggesting that the development of models using both miRNAs and gene markers might improve their prediction performance. In this study miRNAs significantly associated with development of distant metastasis were identified and further investigated and validated in the publicly available dataset from the METABRIC. A combined outcome prediction model using gene expression, miRNA expression and clinico-pathological features was implemented. Fresh-frozen primary tumors were obtained from 123 patients with operable breast cancer previously untreated, pathologically defined as axillary node-negative and undergoing radical or conservative surgery at the Istituto Nazionale Tumori of Milano (INTM) between1990 and 1998. Patients were selected in order to have a comparable pattern of classical risk factors (age, tumor size).
Project description:We identified and validated the pivotal role for a metagene containing IFN-induced genes in association to higher metastatic potential as a function of the specific molecular subtype Fresh frozen primary tumors were collected at the time of diagnosis from 123 patients with operable breast cancer previously untreated and undergoing radical or conservative surgery at the Istituto Nazionale Tumori of Milano (INTM) between1990 and 1998. All patients were pathologically defined as axillary node negative and were not submitted to any type of adjuvant systemic treatment until relapse. Patients were selected in order to have a comparable pattern of classical risk factors (age, tumor size).
Project description:Schmitz2014 - RNA triplex formation
The model is parameterized using the
parameters for gene CCDC3 from Supplementary Table S1. The two
miRNAs which form the triplex together with CCDC3 are miR-551b and
This model is described in the article:
Cooperative gene regulation
by microRNA pairs and their identification using a
Schmitz U, Lai X, Winter F,
Wolkenhauer O, Vera J, Gupta SK.
Nucleic Acids Res. 2014 Jul; 42(12):
MicroRNAs (miRNAs) are an integral part of gene regulation
at the post-transcriptional level. Recently, it has been shown
that pairs of miRNAs can repress the translation of a target
mRNA in a cooperative manner, which leads to an enhanced
effectiveness and specificity in target repression. However, it
remains unclear which miRNA pairs can synergize and which genes
are target of cooperative miRNA regulation. In this paper, we
present a computational workflow for the prediction and
analysis of cooperating miRNAs and their mutual target genes,
which we refer to as RNA triplexes. The workflow integrates
methods of miRNA target prediction; triplex structure analysis;
molecular dynamics simulations and mathematical modeling for a
reliable prediction of functional RNA triplexes and target
repression efficiency. In a case study we analyzed the human
genome and identified several thousand targets of cooperative
gene regulation. Our results suggest that miRNA cooperativity
is a frequent mechanism for an enhanced target repression by
pairs of miRNAs facilitating distinctive and fine-tuned target
gene expression patterns. Human RNA triplexes predicted and
characterized in this study are organized in a web resource at
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Project description:Introduction: MicroRNAs (miRNAs) are small non-coding RNA that play a vital role in cancer progression. Neo-adjuvant chemotherapy (NAC) has become the standard of care for locally advanced breast cancer. The aim of this study was to evaluate miRNA alterations during NAC using multiple samples of tissue and serum to correlate miRNA expression with clinico-pathological features and patient outcomes. Methods: Tissue and serum samples were collected from patients with locally advanced breast cancer undergoing NAC at four time points: time of diagnosis, after the first and fourth cycle of doxorubicin/cyclophosphamide treatment, and after the fourth cycle of docetaxel administration. First, we evaluated the miRNA expression profiles in tissue and correlated expression with clinico-pathological features. Then, a panel of four miRNAs (miR-451, miR-3200, miR-21, and miR-205) in serum samples was further validated using quantitative reverse-transcription polymerase chain reaction (RT-qPCR). The alterations in serum levels of miRNA, associations with clinical and pathological responses, correlation with clinico-pathological features, and survival outcomes were studied using Friedman, Mann-Whitney U, Spearman, Wilcoxon signed-ranks tests. P≤0.05 was considered statistically significant. Results: We analyzed 32 tissue samples and 108 serum samples from 8 patients and 27 patients, respectively. MicroRNA expression profiling of tumor versus normal tissue revealed more than 100 differentially expressed miRNAs. Serum miR-451 levels were significantly decreased during treatment, and higher serum levels were associated with improved clinical and pathological responses and disease-free survival. The serum levels of miR-3200 declined during NAC, and higher serum levels were associated with lower residual breast cancer burden and relapse rates. Conclusion: Variations in serum miRNA levels during NAC treatment may be therapeutically significant for predicting response and survival outcomes. Serum and tissue from a total of 27 consecutive patients diagnosed with locally advanced breast cancer undergoing NAC treatment were collected however microarray data were generated from tissue biopsy of 5 patients at four timepoints for both Normal and tumor. Additionally 3 tissue from only tumor at four timepoints and 6 patients at two timepoint T1 and T4
Project description:CTCs are the purpoted intermediates of metastatic dissemination and are likely to contain cellular clones responsible for disease progression representing a preferred source for identification of druggable targets. Unfortunately a molecular characterization of CTCs is seriously hampered by their low numbers even in metastatic patients and by the elevated contamination of isolated CTCs with leukocytes. With the final goal of providing a reliable assay allowing to obtain valuable information on CTC features in the clinical setting, we have developed a method based on capture with beads linked to EpCAM and to MUC1 exploiting a commercially available kit and performing an extensive gene expression profiling with the DASL platform. For spike-in experiments, low pre-defined numbers of cells derived from established breast cancer cell lines (MCF7 and MDA-MB-468) were spiked into 5 mL of whole blood of healthy donor and captured using AdnaTest EMT-1/StemCell Select kit. Total RNA isolated from the captured cells together with total RNA isolated from the same in vitro cultered cells was processed in duplicate or triplicate onto Illumina Whole-Genome DASL HT platform. Finally, gene expression profiling was carried out on CTCs isolated from blood of 7 patients with advanced breast cancer. According with the characteristics of the study, data normalization was not applicable
Project description:Breast cancers enriched for the triple negative breast cancer phenotype with extensive clinico-pathological features were profiled to establish their comprehensive transcriptional profiles
Project description:Deficiencies in the ATM gene are the underlying cause for ataxia telangiectasia, a congenital syndrome characterized by neurological, motor and immunological defects, as well as a predisposition to cancer risks. MicroRNAs (miRNAs) are small regulators of post-transcriptional gene expression and a useful tool for cancer diagnosis, staging, and prediction of therapeutic responses to clinical regimens. In particular, miRNAs have been used to develop signatures for breast cancer profiling. We are interested in the consequences of ATM deficiency on miRNA expression in breast epithelial cells and the potential contribution to cancer predisposition. In this study we investigate the effects of ATM loss on the miRNA expression and related gene expression changes in normal human mammary epithelial cells (HME-CC). We have identified 81 significantly differently expressed miRNAs in the ATM-deficient HME-CCs using small RNA sequencing. Many of these differentially expressed miRNAs have been described and implicated in tumorigenesis and proliferation. These changes include down-regulation of tumor suppressor miRNAs, such as hsa-miR-29c and hsa-miR-16, as well as the over-expression of pro-oncogenic miRNAs hsa-miR-93 and hsa-mir-221. All 81 miRNAs were combined with genome wide gene expression profiles to investigate possible targets of miRNA regulation. We identified messenger RNA (mRNA) targets of these miRNAs that were also significantly regulated after the depletion of ATM. Predicted targets included many genes implicated in cancer formation and progression, including SOCS1 and the proto-oncogene MAF. Integrated analysis of miRNA and mRNA expression allows us to build a more complete understanding of the pathways and networks involved in the breast cancer predisposition observed in individuals deficient in ATM. This study highlights miRNA and predicted mRNA target expression changes in ATM-deficient HME-CCs and suggests a mechanism for the breast cancer-prone phenotype seen in ATM deficient cells and patients. Additionally, this study provides preliminary data for defining miRNA profiles that may be used prognostic biomarkers for breast cancer predisposition. Examination of small RNA population in human mammary epithelial cell lines. Each condition was preformed in triplicate.
Project description:Breast cancer (BC) in young adult patients (YA), has a more aggressive biological behavior and is associated with a worse prognosis than BC arising in middle aged patients (MA) partly explained by distinct biological features. Deregulated microRNAs (miRs) may had been implicate in modulating genes associated to YA-BC. Objective: Using miRs, their targets mRNA, proteins and stromal genes expression profiles, our aim was to identify differentially expression profiles between tumors from YA and MA. Methodology and results: Samples of ER+ invasive ductal breast carcinomas, divided into 2 groups: YA-BC (35 years or less, n=25) or MA-BC (50-65 years, n=25) were evaluated. All patients indicated low risk of carrying BRCA1/2 mutation. Aggressive characteristics such as large tumor size and advanced histological grade were more evident in YA-BC tumors versus MA-BC. Performing qPCR, we identified 8 miRs differentially expressed (miR-9, 18b, 33b, 106a, 106b, 210, 518a-3p and miR-372) between YA-BC and MA-BC tumors with high confidence statement, which were associated with worse clinico pathological biomarkers. Combined results from in silico prediction with mRNA expression profiles by microarray, identified 602 genes pointing to enriched biological functions related to proliferation, cell cycle and development. Performing RPPA, 24 targets proteins expression differed between both groups. Combination of eight mRNA targets (ESR1, RPS6KA1, YWHAZ, BCL7, PARP12, DUSP2, DUSP8 and PIGS) or the combination of eight target proteins (RAF1, BCL2L1, EIF4E, STAT5A, PARP1, ESR1, RPS6KA1 and YWHAZ) defined an indicator able to classify individual samples into YA-BC or MA-BC groups. A network was belted to protein-protein interaction including regulatory complexity by miRs reveling important biological processes such as proliferation, development and metabolism in YA-BC. Fibroblast-enriched stroma expression profile resulted in 308 stromal genes differentially expressed between YA-BC and MA-BC related to proliferation, differentiation, maturation and metabolism pathways. Conclusion: The differentially expressed miRNAs, their target genes, proteins and stromal genes distinguished early onset from late onset breast cancer and suggested that biological characteristics in YA-BC may be involved with tumor aggressiveness. Overall design: 16 breast tumor from YA group, 13 breast tumors from MA group, 8 stromal breast tumor from YA group and 5 stromal breast tumor from MA group.
Project description:We analyzed gene expression profile in node negative breast tumor for molecular subtype classification Overall design: Fresh frozen primary tumors were collected at the time of diagnosis from 92 patients with operable breast cancer previously untreated and undergoing radical or conservative surgery at the Istituto Nazionale Tumori of Milano (INTM) between1990 and 1998. All patients were pathologically defined as axillary node negative and were not submitted to any type of adjuvant systemic treatment until relapse.
Project description:A subset of breast cancer cells displays increased ability to self-renew and reproduce breast cancer heterogeneity (so called, breast tumour-initiating cells or BT-ICs). As microRNAs (miRNAs) control developmental programs in stem cells, BT-ICs may also rely on specific miRNA profiles for their sustained activity. We analyzed miRNA expression in a model of putative BT-ICs and found that miR-30 family regulates growth under “stemness” conditions. A target screening revealed that miR-30 family modulates the expression of apoptosis and proliferation-related genes. The importance of miR-30 in tumour progression and breast cancer stemness was demonstrated in vivo using a mouse mammary cancer model. This is the first analysis of target prediction in a whole family of microRNAs potentially involved in survival of putative BT-ICs. Total RNA from cells transfected with Pre-miR-30 and KD-miR-30 family and control KD-miR-159 was extracted and reverse-transcribed and hybrized on HT12 Human bead chips
Project description:EORTC 10994 phase III breast cancer clinical trial comparing FEC (5-fluorouracil, cyclophosphamide, epirubicin) with ET (epirubicin, docetaxel). 161 needle biopsies of locally advanced or large operable breast tumours were hybridised to Affymetrix X3P chips. The array data from the ER negative tumours (28/65 pathological CR in the FEC arm, 27/59 pathological CR in the ET arm) were used to validate the cell line-based chemotherapy response predictors developed by the Potti/Nevins group at Duke University (doi:10.1038/nm1491). Experiment Overall Design: We analyzed 161 arrays of breast carcinoma.