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

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.

• 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
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 6 Issue 12 Pg. 1542-60 (Dec 2014) ISSN: 1757-4684 [Electronic] England
• PMID: 25330770 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Enzyme Inhibitors
• Tumor Suppressor Protein p53
• Oncogene Protein v-akt
• Elongation Factor 2 Kinase
• PTEN Phosphohydrolase

Topics

• Animals
• Elongation Factor 2 Kinase (antagonists & inhibitors, genetics, metabolism)
• Enzyme Inhibitors (pharmacology)
• Epithelium (enzymology, metabolism)
• Female
• Gene Deletion
• Humans
• Mammary Glands, Human (enzymology, metabolism)
• Mice
• Mice, Inbred C57BL
• Oncogene Protein v-akt (genetics, metabolism)
• PTEN Phosphohydrolase (genetics, metabolism)
• Triple Negative Breast Neoplasms (drug therapy, enzymology, genetics)
• Tumor Suppressor Protein p53 (genetics, metabolism)