title: 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.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, ON, Canada.
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Liu
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Veronique
authors.initials: V
authors.lastname: Voisin
authors.affiliation: 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.
authors.forename: Sharon
authors.initials: S
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Center, Toronto, ON, Canada Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: Dong-Yu
authors.initials: DY
authors.lastname: Wang
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, ON, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Jones
authors.affiliation: 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.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.affiliation: Drug Discovery Program, Department of Pharmacology and Toxicology, Ontario Institute for Cancer Research, University of Toronto, Toronto, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Uehling
authors.affiliation: Drug Discovery Program, Department of Pharmacology and Toxicology, Ontario Institute for Cancer Research, University of Toronto, Toronto, ON, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Al-awar
authors.affiliation: 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.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Princess Margaret Cancer Center, Toronto, ON, Canada Department of Medical Biophysics, University Health Network, Toronto, ON, Canada.
authors.forename: Ming
authors.initials: M
authors.lastname: Tsao
authors.affiliation: 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.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: 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.
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
mesh_terms: D000818:Animals; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000201:enzymology / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D042361:Mammary Glands, Human / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; D051058:Oncogene Protein v-akt; D054736:Elongation Factor 2 Kinase; D051059:PTEN Phosphohydrolase
keywords: Pten; eEF2K; p53; prognosis; triple‐negative breast cancer