Combined Deletion of Pten and P53 in Mammary Epithelium Accelerates Triple-negative Breast Cancer with Dependency on EEF2K

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2014 Oct 22

PMID 25330770

Citations 60

Authors

Jeff C Liu

Veronique Voisin

Sharon Wang

Dong-Yu Wang

Robert A Jones

Alessandro Datti

David Uehling

Rima Al-Awar

Sean E Egan

Gary D Bader

Ming Tsao

Tak W Mak

Eldad Zacksenhaus

Affiliations

Soon will be listed here.

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.

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