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PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer.

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Date
2016-11
ICR Author
Filosto, Simone
Meier, Pascal
Tutt, Andrew
Cheang, Chon
Buus, Richard
Author
Brasó-Maristany, F
Filosto, S
Catchpole, S
Marlow, R
Quist, J
Francesch-Domenech, E
Plumb, DA
Zakka, L
Gazinska, P
Liccardi, G
Meier, P
Gris-Oliver, A
Cheang, MCU
Perdrix-Rosell, A
Shafat, M
Noël, E
Patel, N
McEachern, K
Scaltriti, M
Castel, P
Noor, F
Buus, R
Mathew, S
Watkins, J
Serra, V
Marra, P
Grigoriadis, A
Tutt, AN
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Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/283
DOI
https://doi.org/10.1038/nm.4198
Collections
  • Breast Cancer Research
  • Cancer Therapeutics
  • Clinical Studies
Subject
Cell Line, Tumor
Mitochondria
Animals
Humans
Mice
Biphenyl Compounds
Proto-Oncogene Proteins c-myc
Proto-Oncogene Proteins c-bcl-2
Protein Kinase Inhibitors
Xenograft Model Antitumor Assays
Neoplasm Transplantation
Apoptosis
Cell Proliferation
Cell Survival
Gene Expression Regulation, Neoplastic
Female
Proto-Oncogene Proteins c-pim-1
Thiazolidines
Gene Knockdown Techniques
DNA Copy Number Variations
Real-Time Polymerase Chain Reaction
Myeloid Cell Leukemia Sequence 1 Protein
Triple Negative Breast Neoplasms
Research team
Cell Death and Immunity
Target Discovery & Apoptosis
Genomic Analysis – Clinical Trials
Language
eng
Date accepted
2016-09-06
License start date
2016-11
Citation
Nature medicine, 2016, 22 (11), pp. 1303 - 1313

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