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dc.contributor.authorMaguire, SL
dc.contributor.authorPeck, B
dc.contributor.authorWai, PT
dc.contributor.authorCampbell, J
dc.contributor.authorBarker, H
dc.contributor.authorGulati, A
dc.contributor.authorDaley, F
dc.contributor.authorVyse, S
dc.contributor.authorHuang, P
dc.contributor.authorLord, CJ
dc.contributor.authorFarnie, G
dc.contributor.authorBrennan, K
dc.contributor.authorNatrajan, R
dc.date.accessioned2016-09-28T13:50:09Z
dc.date.issued2016-11
dc.identifier.citationThe Journal of pathology, 2016, 240 (3), pp. 315 - 328
dc.identifier.issn0022-3417
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/145
dc.identifier.eissn1096-9896
dc.identifier.doi10.1002/path.4778
dc.description.abstractThe initiation and progression of breast cancer from the transformation of the normal epithelium to ductal carcinoma in situ (DCIS) and invasive disease is a complex process involving the acquisition of genetic alterations and changes in gene expression, alongside microenvironmental and recognized histological alterations. Here, we sought to comprehensively characterise the genomic and transcriptomic features of the MCF10 isogenic model of breast cancer progression, and to functionally validate potential driver alterations in three-dimensional (3D) spheroids that may provide insights into breast cancer progression, and identify targetable alterations in conditions more similar to those encountered in vivo. We performed whole genome, exome and RNA sequencing of the MCF10 progression series to catalogue the copy number and mutational and transcriptomic landscapes associated with progression. We identified a number of predicted driver mutations (including PIK3CA and TP53) that were acquired during transformation of non-malignant MCF10A cells to their malignant counterparts that are also present in analysed primary breast cancers from The Cancer Genome Atlas (TCGA). Acquisition of genomic alterations identified MYC amplification and previously undescribed RAB3GAP1-HRAS and UBA2-PDCD2L expressed in-frame fusion genes in malignant cells. Comparison of pathway aberrations associated with progression showed that, when cells are grown as 3D spheroids, they show perturbations of cancer-relevant pathways. Functional interrogation of the dependency on predicted driver events identified alterations in HRAS, PIK3CA and TP53 that selectively decreased cell growth and were associated with progression from preinvasive to invasive disease only when cells were grown as spheroids. Our results have identified changes in the genomic repertoire in cell lines representative of the stages of breast cancer progression, and demonstrate that genetic dependencies can be uncovered when cells are grown in conditions more like those in vivo. The MCF10 progression series therefore represents a good model with which to dissect potential biomarkers and to evaluate therapeutic targets involved in the progression of breast cancer. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
dc.formatPrint
dc.format.extent315 - 328
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectSpheroids, Cellular
dc.subjectHumans
dc.subjectCarcinoma, Ductal, Breast
dc.subjectCarcinoma, Intraductal, Noninfiltrating
dc.subjectBreast Neoplasms
dc.subjectCell Transformation, Neoplastic
dc.subjectDisease Progression
dc.subjectDNA, Neoplasm
dc.subjectSequence Analysis, DNA
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectMutation
dc.subjectGenome
dc.subjectModels, Biological
dc.subjectFemale
dc.subjectTumor Suppressor Protein p53
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectClass I Phosphatidylinositol 3-Kinases
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectTranscriptome
dc.subjectExome
dc.titleThree-dimensional modelling identifies novel genetic dependencies associated with breast cancer progression in the isogenic MCF10 model.
dc.typeJournal Article
dcterms.dateAccepted2016-08-02
rioxxterms.versionofrecord10.1002/path.4778
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-11
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe Journal of pathology
pubs.issue3
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Protein Networks
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular and Systems Oncology
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Protein Networks
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular and Systems Oncology
pubs.publication-statusPublished
pubs.volume240en_US
pubs.embargo.termsNo embargo
icr.researchteamProtein Networksen_US
icr.researchteamFunctional Genomicsen_US
icr.researchteamGene Functionen_US
icr.researchteamMolecular and Systems Oncologyen_US
dc.contributor.icrauthorPeck, Barrieen
dc.contributor.icrauthorVyse, Simonen
dc.contributor.icrauthorHuang, Paulen
dc.contributor.icrauthorLord, Christopheren
dc.contributor.icrauthorNatrajan, Rachaelen
dc.contributor.icrauthorCampbell, Jamesen


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Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0