dc.contributor.author | Brasó-Maristany, F | |
dc.contributor.author | Filosto, S | |
dc.contributor.author | Catchpole, S | |
dc.contributor.author | Marlow, R | |
dc.contributor.author | Quist, J | |
dc.contributor.author | Francesch-Domenech, E | |
dc.contributor.author | Plumb, DA | |
dc.contributor.author | Zakka, L | |
dc.contributor.author | Gazinska, P | |
dc.contributor.author | Liccardi, G | |
dc.contributor.author | Meier, P | |
dc.contributor.author | Gris-Oliver, A | |
dc.contributor.author | Cheang, MCU | |
dc.contributor.author | Perdrix-Rosell, A | |
dc.contributor.author | Shafat, M | |
dc.contributor.author | Noël, E | |
dc.contributor.author | Patel, N | |
dc.contributor.author | McEachern, K | |
dc.contributor.author | Scaltriti, M | |
dc.contributor.author | Castel, P | |
dc.contributor.author | Noor, F | |
dc.contributor.author | Buus, R | |
dc.contributor.author | Mathew, S | |
dc.contributor.author | Watkins, J | |
dc.contributor.author | Serra, V | |
dc.contributor.author | Marra, P | |
dc.contributor.author | Grigoriadis, A | |
dc.contributor.author | Tutt, AN | |
dc.date.accessioned | 2016-11-24T13:57:28Z | |
dc.date.issued | 2016-11-01 | |
dc.identifier.citation | Nature medicine, 2016, 22 (11), pp. 1303 - 1313 | |
dc.identifier.issn | 1078-8956 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/283 | |
dc.identifier.eissn | 1546-170X | |
dc.identifier.doi | 10.1038/nm.4198 | |
dc.description.abstract | Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death. | |
dc.format | Print-Electronic | |
dc.format.extent | 1303 - 1313 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.subject | Cell Line, Tumor | |
dc.subject | Mitochondria | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Biphenyl Compounds | |
dc.subject | Proto-Oncogene Proteins c-myc | |
dc.subject | Proto-Oncogene Proteins c-bcl-2 | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Neoplasm Transplantation | |
dc.subject | Apoptosis | |
dc.subject | Cell Proliferation | |
dc.subject | Cell Survival | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Female | |
dc.subject | Proto-Oncogene Proteins c-pim-1 | |
dc.subject | Thiazolidines | |
dc.subject | Gene Knockdown Techniques | |
dc.subject | DNA Copy Number Variations | |
dc.subject | Real-Time Polymerase Chain Reaction | |
dc.subject | Myeloid Cell Leukemia Sequence 1 Protein | |
dc.subject | Triple Negative Breast Neoplasms | |
dc.title | PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-09-06 | |
rioxxterms.versionofrecord | 10.1038/nm.4198 | |
rioxxterms.licenseref.startdate | 2016-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature medicine | |
pubs.issue | 11 | |
pubs.notes | 6 months | |
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/Cell Death and Immunity | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Target Discovery & Apoptosis | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Discovery & Apoptosis | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Genomic Analysis – Clinical Trials | |
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/Cell Death and Immunity | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Target Discovery & Apoptosis | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Discovery & Apoptosis | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Genomic Analysis – Clinical Trials | |
pubs.publication-status | Published | |
pubs.volume | 22 | |
pubs.embargo.terms | 6 months | |
icr.researchteam | Cell Death and Immunity | |
icr.researchteam | Target Discovery & Apoptosis | |
icr.researchteam | Genomic Analysis – Clinical Trials | |
dc.contributor.icrauthor | Filosto, Simone | |
dc.contributor.icrauthor | Meier, Pascal | |
dc.contributor.icrauthor | Cheang, Chon | |
dc.contributor.icrauthor | Buus, Richard | |
dc.contributor.icrauthor | Tutt, Andrew | |