Reproductive history determines ErbB2 locus amplification, WNT signalling and tumor phenotype in a murine breast cancer model
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PROVIDER: PRJNA681569 | ENA |
REPOSITORIES: ENA
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Project description:Understanding the mechanisms underlying tumor heterogeneity is key to development of treatments that can target specific tumor subtypes. We have previously targeted CRE recombinase-dependent conditional deletion of the tumor suppressor genes Brca1, Brca2, p53 and/or Pten to basal or luminal ER- cells of the mouse mammary epithelium. We demonstrated that both the cell-of-origin and the tumor-initiating genetic lesions co-operate to influence mammary tumor phenotype. Here, we use a CRE-activated HER2 orthologue to specifically target HER2/ERBB2 oncogenic activity to basal or luminal ER- mammary epithelial cells and carry out a detailed analysis of the tumors which develop. We find that in contrast to our previous studies, basal epithelial cells are refractory to transformation by the activated NeuKI allele, with mammary epithelial tumor formation largely confined to luminal ER- cells. Histologically, the majority of tumors that developed were classified as either adenocarcinomas of no special type or metaplastic adenosquamous tumors. Remarkably, the former were more strongly associated with virgin animals and were typically characterised by amplification of the NeuNT/ErbB2 locus and activation of non-canonical WNT signalling. In contrast, tumors characterised by squamous metaplasia were associated with animals that had been through at least one pregnancy and typically had lower levels of NeuNT/ErbB2 locus amplification but had activated canonical WNT signalling. Squamous changes in these tumors were associated with activation of the Epidermal Differentiation Cluster. Thus, in this model of HER2 breast cancer, cell-of-origin, reproductive history, NeuNT/ErbB2 locus amplification, and the activation of specific branches of the WNT signalling pathway all interact to drive inter-tumor heterogeneity.
2020-12-01 | GSE162347 | GEO
Project description:Understanding the mechanisms underlying tumor heterogeneity is key to development of treatments that can target specific tumor subtypes. We have previously targeted CRE recombinase-dependent conditional deletion of the tumor suppressor genes Brca1, Brca2, p53 and/or Pten to basal or luminal ER- cells of the mouse mammary epithelium. We demonstrated that both the cell-of-origin and the tumor-initiating genetic lesions co-operate to influence mammary tumor phenotype. Here, we use a CRE-activated HER2 orthologue to specifically target HER2/ERBB2 oncogenic activity to basal or luminal ER- mammary epithelial cells and carry out a detailed analysis of the tumors which develop. We find that in contrast to our previous studies, basal epithelial cells are refractory to transformation by the activated NeuKI allele, with mammary epithelial tumor formation largely confined to luminal ER- cells. Histologically, the majority of tumors that developed were classified as either adenocarcinomas of no special type or metaplastic adenosquamous tumors. Remarkably, the former were more strongly associated with virgin animals and were typically characterised by amplification of the NeuNT/ErbB2 locus and activation of non-canonical WNT signalling. In contrast, tumors characterised by squamous metaplasia were associated with animals that had been through at least one pregnancy and typically had lower levels of NeuNT/ErbB2 locus amplification but had activated canonical WNT signalling. Squamous changes in these tumors were associated with activation of the Epidermal Differentiation Cluster. Thus, in this model of HER2 breast cancer, cell-of-origin, reproductive history, NeuNT/ErbB2 locus amplification, and the activation of specific branches of the WNT signalling pathway all interact to drive inter-tumor heterogeneity.
2020-11-12 | GSE161282 | GEO
Project description:Reproductive history determines ErbB2 locus amplification, WNT signalling and tumor phenotype in a murine breast cancer model [exome sequencing]
| PRJNA681573 | ENA
Project description:Reproductive history determines ErbB2 locus amplification, WNT signalling and tumor phenotype in a murine breast cancer model [RNA-seq]
| PRJNA676125 | ENA
Project description:Understanding the mechanisms underlying tumour heterogeneity is key to the development of treatments that can target specific tumour subtypes. We have previously targeted CRE recombinase-dependent conditional deletion of the tumour suppressor genes Brca1, Brca2, p53 (also known as Trp53) and/or Pten to basal or luminal oestrogen receptor-negative (ER-) cells of the mouse mammary epithelium. We demonstrated that both the cell-of-origin and the tumour-initiating genetic lesions cooperate to influence mammary tumour phenotype. Here, we use a CRE-activated HER2 orthologue to specifically target HER2/ERBB2 oncogenic activity to basal or luminal ER- mammary epithelial cells and perform a detailed analysis of the tumours that develop. We find that, in contrast to our previous studies, basal epithelial cells are less sensitive to transformation by the activated NeuKI allele, with mammary epithelial tumour formation largely confined to luminal ER- cells. Histologically, most tumours that developed were classified as either adenocarcinomas of no special type or as metaplastic adenosquamous tumours. The former were typically characterized by amplification of the NeuNT/Erbb2 locus; in contrast, tumours displaying squamous metaplasia were enriched in animals that had been through at least one pregnancy and typically had lower levels of NeuNT/Erbb2 locus amplification but had activated canonical WNT signalling. Squamous changes in these tumours were associated with activation of the epidermal differentiation cluster. Thus, in this model of HER2 breast cancer, cell-of-origin, reproductive history, NeuNT/Erbb2 locus amplification and the activation of specific branches of the WNT signalling pathway all interact to drive inter-tumour heterogeneity.
| S-EPMC8188886 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-11-30 | GSE162348 | GEO
Project description:Oesophageal adenocarcinoma (OAC) is a deadly disease with poor survival statistics and few targeted therapies available. One of the most common molecular aberrations in OAC is amplification or activation of the receptor tyrosine kinase ERBB2, and ERBB2 is targeted in the clinic for this subset of patients. However, the downstream consequences of these activating events ERBB2 activation or amplification are not well understood. Here we used a combination of phosphoproteomics, open chromatin profiling and transcriptome analysis on cell line models and patient-derived datasets to interrogate the molecular pathways operating downstream from ERBB2. Integrated analysis of these data sets converge on a model where ERBB2 activity is mediated at the transcriptional level by the transcription factor AP1. AP1 in turn controls cell behaviour by acting on cohorts of genes that regulate cell migration and adhesion, features often associated with EMT. Our study therefore provides a valuable resource for the cancer cell signalling community and reveals novel molecular determinants underlying the dysregulated behaviour of OAC cells.
2023-01-03 | PXD029180 | Pride
Project description:The mechanisms of ErbB2 signalling and the effects of its overexpression are not fully understood. Herein, SILAC expression profiling and phosphopeptide enrichment of a relevant, non-transformed, immortalized human mammary luminal epithelial cell model were used to profile ErbB2-dependent differences in protein expression and phosphorylation events triggered via EGFR (EGF treatment) and ErbB3 (HRGbeta1 treatment) in the context of ErbB2 overexpression. Bioinformatics analysis was used to infer changes in cellular processes and signalling events. We demonstrate the complexity of the responses to oncogene expression and growth factor signalling and identify protein changes relevant to ErbB2-dependent altered cellular phenotype, in particular cell cycle progression and hyper-proliferation, reduced adhesion and enhanced motility. Numerous novel sites of growth factor-regulated phosphorylation were also identified that were enhanced by ErbB2 overexpression and we putatively link these to altered cell behaviour. Moreover, we have defined a novel mechanism by which ErbB signalling suppresses basal interferon signalling that would promote the survival and proliferation of mammary luminal epithelial cells.
2018-10-26 | PXD004195 | Pride
Project description:Although ERBB2 amplification and overexpression is correlated with poor outcome in breast cancer, the molecular mechanisms underlying the aggressive nature of these tumors has not been fully elucidated. To investigate this further, we have used a transgenic mouse model of ErbB2-driven tumor progression (ErbB2KI model) that recapitulates clinically relevant events, including selective amplification of the core erbB2 amplicon. By comparing the transcriptional profiles of ErbB2KI mammary tumors and human ERBB2-positive breast cancers, we demonstrate that ErbB2KI tumors possess molecular features of the basal subtype of ERBB2-positive human breast cancer, including activation of canonical β-catenin signaling. Inhibition of β-catenin-dependent signaling in ErbB2KI-derived tumor cells using RNA interference impaired tumor initiation and metastasis. Furthermore, treatment of ErbB2KI or human ERBB2-overexpressing tumor cells with a selective β-catenin/CBP inhibitor significantly decreased proliferation and ErbB2 expression. Collectively, our data indicate that ERBB2-mediated breast cancer progression requires β-catenin signaling and can be therapeutically targeted by selective β-catenin/CBP inhibitors.
2013-06-02 | GSE37954 | GEO
Project description:The ERBB family consists of four receptors (EGFR, ERBB2, ERBB3, and ERBB4) that are critical in normal development and physiology of mammalian gastrointestinal epithelial tissues. Amplifications or mutations in ERBB2 are commonly found in CRC, suggesting a possible therapeutic target. Patients with ERBB2-amplification in breast and gastroesophageal cancer are routinely treated with the ERBB2-directed antibody trastuzumab. However, ERBB2 is not commonly targeted in clinical practice of treating CRC. Notably, ERBB2 status could guide therapy as a negative marker for EGFR-targeted therapy (cetuximab) and identify likely responders for ERBB2-directed therapy. Although the most common marker for negative efficacy of anti-EGFR therapy is KRAS mutations, many patients with KRAS wild-type tumors do not respond to EGFR inhibition. As the primary EGFR-directed antibodies for CRC do not inhibit ERBB2, alterations increasing ERBB2 may serve as a superior negative predictor of EGFR therapy since previous studies demonstrate that ERBB2 amplification confers resistance to cetuximab in preclinical models. Despite the compelling evidence, the utility of ERBB2 as a target for molecular therapy of primary CRC tumors in preclinical models is largely unexplored. As such, our goal is to further characterize the influece of ERBB2 in the initiation and progression of CRC.
2024-08-16 | GSE241084 | GEO