PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer.
MetadataShow full item record
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.
Version of record
Cell Line, Tumor
DNA Copy Number Variations
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Myeloid Cell Leukemia Sequence 1 Protein
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-2
Proto-Oncogene Proteins c-myc
Proto-Oncogene Proteins c-pim-1
Real-Time Polymerase Chain Reaction
Triple Negative Breast Neoplasms
Xenograft Model Antitumor Assays
Cell Death and Inflammation
Target Discovery & Apoptosis
Genomic Analysis – Clinical Trials
License start date
Nat Med, 2016, 22 (11), pp. 1303 - 1313
Showing items related by title, author, creator and subject.
Mardakheh, FK; Self, A; Marshall, CJ (2016-12-15)Directional cell migration involves reorientation of the secretory machinery. However, the molecular mechanisms that control this reorientation are not well characterised. Here, we identify a new Rho effector protein, named ...
International Cancer Genome Consortium PedBrain Tumor Project (2016-11)Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously ...
Ecdysone-inducible expression of oncogenic Ha-Ras in NIH 3T3 cells leads to transient nuclear localization of activated extracellular signal-regulated kinase regulated by mitogen-activated protein kinase phosphatase-1. Plows, D; Briassouli, P; Owen, C; Zoumpourlis, V; Garrett, MD; Pintzas, A (2002-03)The Ras family of GTP-binding proteins are key transducers of extracellular signals, particularly through the mitogen-activated protein kinase (MAPK) pathway. Constitutively active forms of Ras are found in a variety of ...