Role of endogenous type I Interferon in spontaneous, Her2/Neu oncogene-driven carcinogenesis
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PROVIDER: PRJNA433517 | ENA |
REPOSITORIES: ENA
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Project description:Type I Interferons (IFN-I) are anti-viral and immuno-modulating cytokines involved in many steps across tumor initiation and progression. IFN-I act directly on tumor cells inhibiting cell growth and indirectly by activating immune cells to mount antitumor response. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in Her2/neu transgenic (neuT) mice carrying a non-functional mutation in the IFN-I receptor (IFNAR1), thus being unresponsive to this family of cytokines. Compared to parental neu+/-mice (neuT mice), IFNAR1-/- neu+/- mice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. Of note, IFNAR-neuT tumors specifically exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including breast cancer stem cells (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1). An increased amount of BCSC was observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay and tumorigenic capacity. In vitro exposure of neuT+ mammospheres and cell lines to anti-IFN-I antibodies resulted in increased frequency of ALDH+ cells, suggesting that IFN-I control stemness in tumor cells. Altogether, these results reveal an essential role of IFN-I in NeuT-driven spontaneous carcinogenesis through intrinsic control of BCSC.
2018-05-22 | GSE110350 | GEO
Project description:HER2 / Neu is amplified and overexpressed in a large proportion of human breast cancers, but the signaling pathways that contribute to tumor development and metastatic progression are not completely understood. Using gene expression data and pathway signatures we predicted a role for activator E2F transcription factors in Neu induced tumors. This was genetically tested by interbreeding Neu transgenics with knockouts of the three activator E2Fs. Loss of any E2F delayed Neu induced tumor onset. E2F1 loss accelerated tumor growth while E2F2 and E2F3 loss did not. Strikingly, it was observed that loss of E2F1 or E2F2 significantly reduced the metastatic capacity of the tumor and this was associated with a reduction in circulating tumor cells in the E2F2 knockout. Gene expression analysis between the tumors in the various E2F mutant backgrounds revealed that there was extensive compensation by other E2F family members in the individual knockouts, underscoring the importance of the E2Fs in HER2 / Neu induced tumors. Extension to HER2 positive human breast cancer revealed a number of HER2+ subtypes based on E2F activity with differences in relapse free survival times. Taken together these data demonstrate that the E2F transcription factors are integral to HER2+ tumor development and progression.
2014-12-29 | GSE42533 | GEO
Project description:Breast cancer is a heterogeneous disease encompassing a number of phenotypically diverse tumours. Expression levels of the estrogen, progesterone and HER2/neu receptors which characterise clinically distinct breast tumors have been shown to change during disease progression and in response to systemic therapies. Mi(cro)RNAs play critical roles in diverse biological processes and are aberrantly expressed in several human neoplasms including breast cancer, where they function as regulators of tumour behaviour and progression. The aims of this study were to identify miRNA signatures that accurately predict the oestrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor status of breast cancer patients to provide insight into the regulation of breast cancer phenotypes and progression. Expression profiling of 353 microRNAs was performed in 29 early stage breast cancer specimens. MiRNA signatures associated with ER, PR and HER2/neu status were generated using artificial neural networks (ANN) and expression of specific microRNAs was validated using RQ-PCR. Results: Stepwise artificial neural network (ANN) analysis identified predictive miRNA signatures corresponding with estrogen (miR-342, miR-299, miR-217, miR -190, miR-135b, miR-218), progesterone (miR-520g, miR-377, miR-527-518a, miR-520f-520c) and HER2/neu (miR-520d, miR-181c, miR-302c, miR-376b, miR-30e) receptor status. MiR-342 and miR-520g expression was further analysed in 95 breast tumours. MiR-342 expression was highest in ER and HER2/neu positive luminal B tumours and lowest in triple-negative tumours. MiR-520g expression was elevated in ER and PR negative tumours.
2010-05-18 | E-GEOD-15885 | biostudies-arrayexpress
Project description:To identify early events of erbB2-induced mammary tumorigenesis, we compared datasets from 14 genechip experiments including MMTV-neu tumors, preneoplastic neu mammary gland (adjacent neu), and age-matched, wild-type control mammary glands Keywords = transgenic mouse Keywords = MMTV-neu Keywords = erbB2 Keywords = HER2 Keywords = mammary tumor Keywords: ordered
2005-05-03 | GSE2528 | GEO
Project description:Breast cancer is a heterogeneous disease encompassing a number of phenotypically diverse tumours. Expression levels of the estrogen, progesterone and HER2/neu receptors which characterise clinically distinct breast tumors have been shown to change during disease progression and in response to systemic therapies. Mi(cro)RNAs play critical roles in diverse biological processes and are aberrantly expressed in several human neoplasms including breast cancer, where they function as regulators of tumour behaviour and progression. The aims of this study were to identify miRNA signatures that accurately predict the oestrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor status of breast cancer patients to provide insight into the regulation of breast cancer phenotypes and progression.
2009-05-21 | GSE15885 | GEO
Project description:Murine models of mammary cancers have proven to be highly informative on numerous fronts including individual gene causation, microenvironmental analyses, and chemoprevention studies. The MMTV-Neu transgenic model of mammary cancer has proven to be a useful model and has been employed in several prevention studies. However, there are certain practical drawbacks to its use including long tumor latencies and a tendency to develop mutations in the transmembrane domain of Neu (unlike human HER2/Neu overexpressing breast cancers). Here we report modifications that were made in an attempt to optimize this mouse model for chemopreventive screening. First, homozygous MMTV-Neu and homozygous P53 KO mice were crossed to create a MMTV-Neu/P53+/- strain (which more closely approximates the genetic make-up of most HER2+ human patients). Second, to overcome the drawback of long tumor latencies, the mice were treated with DMBA for eight weeks. DMBA treatment greatly decreased the latency of mammary carcinomas in the MMTV-Neu mice although the resulting tumors remained histopathologically similar to those from MMTV-Neu control mice. Next, we examined gene expression in tumors derived from MMTV-Neu, MMTV-Neu/p53+/-, and DMBA treated mice. It was found that the characteristic MMTV-Neu tumor-defined expression pattern was still the most prevalent feature of all the MMTV-Neu tumors despite their being crossed to the p53 null allele, treated with DMBA, or both. However, tumors from the DMBA treated animals exhibited many unique gene expression changes including the high expression of stress response, defense, and inflammation genes. Finally, we demonstrated that the RXR agonists UAB30 and Targretin, both inhibited mammary cancer formation in MMTV-Neu mice, including those treated with DMBA. These results demonstrate the potential utility of this murine model for additional chemoprevention studies.
2021-01-31 | GSE35188 | GEO
Project description:Transcriptional expression of a restricted set of cancer signal transduction-related gesen were comparatively quantified in HER2/neu transgenic mammary tumors, mesenchymal and epithelial tumor cell lineages, both estabilished from HER-2/neu transgenic tumors, and syngeneic mesenchymal stem cells. In the study presented here, HER-2/neu transgenic mouse mammary tumors, previously described (Galie et al Carcinogenesis 2005 26(11):1868) mesenchymal (A17) and epithelial (BB1) cell lineages estabilished from murine HER-2/neu transgenic mammary tumors, and syngeneic mesenchymal stem cells, underwent transcriptional analysis using microarrays containing probes for 112 signal transduction-related genes and controls (GEArray Q Series Mouse Signal Transduction in Cancer Gene Array, MM-044, Superarray, Friederick, MD, USA).
2010-07-03 | E-GEOD-22663 | biostudies-arrayexpress
Project description:V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2; synonyms HER2, NEU) encodes a transmembrane glycoprotein with tyrosine kinase-specific activity that acts as a major switch in different signal-transduction processes. ERBB2 amplification and overexpression have been found in a number of human cancers, including breast, ovary and kidney carcinoma. Our aim was to detect ERBB2- regulated target genes that contribute to its tumorigenic effect on a genomewide scale. The differential gene expression profile of ERBB2- transfected and wild-type mouse fibroblasts was monitored employing DNA microarrays. Regulated expression of selected genes was verified by RT-PCR and validated by Western blot analysis. Genomewide gene expression profiling identified (i) known targets of ERBB2 signaling, (ii) genes implicated in tumorigenesis but so far not associated with ERBB2 signaling as well as (iii) genes not yet associated with oncogenic transformation, including novel genes without functional annotation. We also found that at least a fraction of coexpressed genes are closely linked on the genome. ERBB2 overexpression suppresses the transcription of antiangiogenic factors (e.g., Sparc, Timp3, Serpinf1) but induces expression of angiogenic factors (e.g., Klf5, Tnfaip2, Sema3c). Profiling of ERBB2-dependent gene regulation revealed a compendium of potential diagnostic markers and putative therapeutic targets. Identification of coexpressed genes that colocalize in the genome may indicate gene regulatory mechanisms that require further study to evaluate functional coregulation. Erbb2 transfected NIH3T3 cells versus un-transfected cells, 4 technical replicates including two colour swap experiments
2010-06-25 | E-GEOD-16445 | biostudies-arrayexpress
Project description:Purpose: We generated extensive transcriptional and proteomic profiles from a Her2-driven mouse model of breast cancer that closely recapitulates human breast cancer. This report makes these data publicly available in raw and processed forms, as a resource to the community. Importantly, we previously made biospecimens from this same mouse model freely available through a sample repository, so researchers can obtain samples to test biological hypotheses without the need of breeding animals and collecting biospecimens. Experimental design: Twelve datasets are available, encompassing 841 LC-MS/MS experiments (plasma and tissues) and 255 microarray analyses of multiple tissues (thymus, spleen, liver, blood cells, and breast). Cases and controls were rigorously paired to avoid bias. Results: In total, 18,880 unique peptides were identified (PeptideProphet peptide error rate â¤1%), with 3884 and 1659 non-redundant protein groups identified in plasma and tissue datasets, respectively. Sixty-one of these protein groups overlapped between cancer plasma and cancer tissue. Conclusions and clinical relevance: These data are of use for advancing our understanding of cancer biology, for software and quality control tool development, investigations of analytical variation in MS/MS data, and selection of proteotypic peptides for MRM-MS. The availability of these datasets will contribute positively to clinical proteomics. Custom Agilent 44K whole mouse genome expression oligonucleotide microarrays were used to profile breast tumors from three Her2/Neu mice compared to normal breast epithelium from two control mice transgenic for TetO-NeuNT only and littermates of the bitransgenic mice. All samples were laser-capture microdissected and total RNA isolated and amplified prior to hybridization against a reference pool of normal adult mouse tissues.
2010-10-18 | E-GEOD-20280 | biostudies-arrayexpress
Project description:V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2; synonyms HER2, NEU) encodes a transmembrane glycoprotein with tyrosine kinase-specific activity that acts as a major switch in different signal-transduction processes. ERBB2 amplification and overexpression have been found in a number of human cancers, including breast, ovary and kidney carcinoma. Our aim was to detect ERBB2- regulated target genes that contribute to its tumorigenic effect on a genomewide scale. The differential gene expression profile of ERBB2- transfected and wild-type mouse fibroblasts was monitored employing DNA microarrays. Regulated expression of selected genes was verified by RT-PCR and validated by Western blot analysis. Genomewide gene expression profiling identified (i) known targets of ERBB2 signaling, (ii) genes implicated in tumorigenesis but so far not associated with ERBB2 signaling as well as (iii) genes not yet associated with oncogenic transformation, including novel genes without functional annotation. We also found that at least a fraction of coexpressed genes are closely linked on the genome. ERBB2 overexpression suppresses the transcription of antiangiogenic factors (e.g., Sparc, Timp3, Serpinf1) but induces expression of angiogenic factors (e.g., Klf5, Tnfaip2, Sema3c). Profiling of ERBB2-dependent gene regulation revealed a compendium of potential diagnostic markers and putative therapeutic targets. Identification of coexpressed genes that colocalize in the genome may indicate gene regulatory mechanisms that require further study to evaluate functional coregulation.
2009-06-10 | GSE16445 | GEO