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EMBO Mol Med. 2014 Dec;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

1
Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, ON, Canada.
2
The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
3
Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, ON, Canada Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada.
4
Princess Margaret Cancer Center, Toronto, ON, Canada Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, ON, Canada.
5
SMART 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.
6
Drug Discovery Program, Department of Pharmacology and Toxicology, Ontario Institute for Cancer Research, University of Toronto, Toronto, ON, Canada.
7
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
8
The Donnelly Centre, University of Toronto, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
9
Princess Margaret Cancer Center, Toronto, ON, Canada Department of Medical Biophysics, University Health Network, Toronto, ON, Canada.
10
Campbell 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.
11
Division 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
[Indexed for MEDLINE]
Free PMC Article

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