File Download
Links for fulltext
(May Require Subscription)
- Publisher Website: 10.15252/emmm.201404402
- Scopus: eid_2-s2.0-84918591915
- PMID: 25330770
- WOS: WOS:000345915400007
- Find via
Supplementary
- Citations:
- Appears in Collections:
Article: Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K
Title | Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K |
---|---|
Authors | |
Keywords | eEF2K Pten Triple-negative breast cancer P53 Prognosis |
Issue Date | 2014 |
Citation | EMBO Molecular Medicine, 2014, v. 6, n. 12, p. 1542-1560 How to Cite? |
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. |
Persistent Identifier | http://hdl.handle.net/10722/292856 |
ISSN | 2023 Impact Factor: 9.0 2023 SCImago Journal Rankings: 3.964 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Liu, Jeff C. | - |
dc.contributor.author | Voisin, Veronique | - |
dc.contributor.author | Wang, Sharon | - |
dc.contributor.author | Wang, Dong Yu | - |
dc.contributor.author | Jones, Robert A. | - |
dc.contributor.author | Datti, Alessandro | - |
dc.contributor.author | Uehling, David | - |
dc.contributor.author | Al-awar, Rima | - |
dc.contributor.author | Egan, Sean E. | - |
dc.contributor.author | Bader, Gary D. | - |
dc.contributor.author | Tsao, Ming | - |
dc.contributor.author | Mak, Tak W. | - |
dc.contributor.author | Zacksenhaus, Eldad | - |
dc.date.accessioned | 2020-11-17T14:57:21Z | - |
dc.date.available | 2020-11-17T14:57:21Z | - |
dc.date.issued | 2014 | - |
dc.identifier.citation | EMBO Molecular Medicine, 2014, v. 6, n. 12, p. 1542-1560 | - |
dc.identifier.issn | 1757-4676 | - |
dc.identifier.uri | http://hdl.handle.net/10722/292856 | - |
dc.description.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. | - |
dc.language | eng | - |
dc.relation.ispartof | EMBO Molecular Medicine | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | eEF2K | - |
dc.subject | Pten | - |
dc.subject | Triple-negative breast cancer | - |
dc.subject | P53 | - |
dc.subject | Prognosis | - |
dc.title | Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K | - |
dc.type | Article | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.15252/emmm.201404402 | - |
dc.identifier.pmid | 25330770 | - |
dc.identifier.pmcid | PMC4287974 | - |
dc.identifier.scopus | eid_2-s2.0-84918591915 | - |
dc.identifier.volume | 6 | - |
dc.identifier.issue | 12 | - |
dc.identifier.spage | 1542 | - |
dc.identifier.epage | 1560 | - |
dc.identifier.eissn | 1757-4684 | - |
dc.identifier.isi | WOS:000345915400007 | - |
dc.identifier.issnl | 1757-4676 | - |