Format

Send to

Choose Destination
See comment in PubMed Commons below
EMBO Mol Med. 2014 Oct 20;6(12):1542-60. doi: 10.15252/emmm.201404402.

Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K.

Author information

  • 1Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, ON, Canada.
  • 2The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
  • 3Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, ON, Canada Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada.
  • 4Princess Margaret Cancer Center, Toronto, ON, Canada Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, ON, Canada.
  • 5SMART Laboratory for High-Throughput Screening Programs, Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON, Canada Department of Agricultural, Food and Environmental Sciences, University of Perugia, Perugia, Italy.
  • 6Drug Discovery Program, Department of Pharmacology and Toxicology, Ontario Institute for Cancer Research, University of Toronto, Toronto, ON, Canada.
  • 7Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 8The Donnelly Centre, University of Toronto, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 9Princess Margaret Cancer Center, Toronto, ON, Canada Department of Medical Biophysics, University Health Network, Toronto, ON, Canada.
  • 10Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, ON, Canada SMART Laboratory for High-Throughput Screening Programs, Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON, Canada Department of Medical Biophysics, University Health Network, Toronto, ON, Canada.
  • 11Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, ON, Canada Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada Department of Medical Biophysics, University Health Network, Toronto, ON, Canada eldad.zacksenhaus@utoronto.ca.

Abstract

The tumor suppressors Pten and p53 are frequently lost in breast cancer, yet the consequences of their combined inactivation are poorly understood. Here, we show that mammary-specific deletion of Pten via WAP-Cre, which targets alveolar progenitors, induced tumors with shortened latency compared to those induced by MMTV-Cre, which targets basal/luminal progenitors. Combined Pten-p53 mutations accelerated formation of claudin-low, triple-negative-like breast cancer (TNBC) that exhibited hyper-activated AKT signaling and more mesenchymal features relative to Pten or p53 single-mutant tumors. Twenty-four genes that were significantly and differentially expressed between WAP-Cre:Pten/p53 and MMTV-Cre:Pten/p53 tumors predicted poor survival for claudin-low patients. Kinome screens identified eukaryotic elongation factor-2 kinase (eEF2K) inhibitors as more potent than PI3K/AKT/mTOR inhibitors on both mouse and human Pten/p53-deficient TNBC cells. Sensitivity to eEF2K inhibition correlated with AKT pathway activity. eEF2K monotherapy suppressed growth of Pten/p53-deficient TNBC xenografts in vivo and cooperated with doxorubicin to efficiently kill tumor cells in vitro. Our results identify a prognostic signature for claudin-low patients and provide a rationale for using eEF2K inhibitors for treatment of TNBC with elevated AKT signaling.

KEYWORDS:

Pten; eEF2K; p53; prognosis; triple‐negative breast cancer

PMID:
25330770
PMCID:
PMC4287974
DOI:
10.15252/emmm.201404402
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center