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

EMBO Molecular Medicine

Jeff C Liu¹  Veronique Voisin²  Sharon Wang¹  Dong-Yu Wang⁴  Robert A Jones¹  Alessandro Datti⁵  David Uehling⁶  Rima Al-awar⁶  Sean E Egan³  Gary D Bader²  Ming Tsao⁴  Tak W Mak⁷ 

[1] Division of Advanced Diagnostics, Toronto General Research Institute – University Health Network, Toronto, ON, Canada;The Donnelly Centre, University of Toronto, Toronto, ON, Canada;Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada;Princess Margaret Cancer Center, Toronto, ON, Canada;SMART Laboratory for High-Throughput Screening Programs, Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON, Canada;Drug Discovery Program, Department of Pharmacology and Toxicology, Ontario Institute for Cancer Research, University of Toronto, Toronto, ON, Canada;Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, ON, Canada

关键词: eEF2K;    p53;    prognosis;    Pten;    triple‐negative breast cancer;   

DOI  :  10.15252/emmm.201404402

来源: Wiley

【 摘 要 】

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.

Synopsis

The tumor suppressors Pten and p53 are frequently lost in triple-negative breast cancer (TNBC). In double mouse KO, tumors identity changed to a sarcomatoid/mesenchymal subtype; molecular and bioinformatics analyses revealed eEF2K as a potential therapeutic target.

• Disruption of Pten and p53 via MMTV-Cre or WAP-Cre accelerated formation of claudin-low-like TNBC.
• A 24-gene set that discriminates Pten/p53-deficient tumors driven by MMTV-Cre versus WAP-Cre transgenes could predict clinical outcome for claudin-low TNBC patients.
• Kinome screen identified eEF2K inhibitors as most potent growth suppressors for both mouse and human Pten/p53-deficient TNBC.
• eEF2K inhibitors might represent a novel therapy for Pten/p53-deficient TNBC with high AKT signaling.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.