Liu Jeff C, Voisin Veronique, Wang Sharon, Wang Dong-Yu, Jones Robert A, Datti Alessandro, Uehling David, Al-awar Rima, Egan Sean E, Bader Gary D, Tsao Ming, Mak Tak W, Zacksenhaus Eldad
Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, ON, Canada.
The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
EMBO Mol Med. 2014 Dec;6(12):1542-60. doi: 10.15252/emmm.201404402.
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.
肿瘤抑制因子Pten和p53在乳腺癌中经常缺失，但其联合失活的后果却知之甚少。在这里，我们表明，通过靶向肺泡祖细胞的WAP-Cre进行乳腺特异性Pten缺失，与靶向基底/管腔祖细胞的MMTV-Cre诱导的肿瘤相比，诱导肿瘤的潜伏期缩短。Pten-p53联合突变加速了claudin-low、三阴性样乳腺癌（TNBC）的形成，相对于Pten或p53单突变肿瘤，该肿瘤表现出超激活的AKT信号和更多的间充质特征。在WAP-Cre:Pten/p53和MMTV-Cre:Pten/p53肿瘤之间显著差异表达的24个基因预测claudin-low患者的生存率较低。激酶组筛选确定真核延伸因子-2激酶（eEF2K）抑制剂在小鼠和人类Pten/p53缺陷的TNBC细胞上比PI3K/AKT/mTOR抑制剂更有效。对eEF2K抑制的敏感性与AKT途径活性相关。eEF2K单一疗法在体内抑制Pten/p53缺陷的TNBC异种移植瘤的生长，并与阿霉素协同作用在体外有效杀死肿瘤细胞。我们的结果确定了claudin-low患者的预后特征，并为使用eEF2K抑制剂治疗AKT信号升高的TNBC提供了理论依据。
