Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer.
Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer.
复制标题
含有死亡效应结构域的蛋白质诱导三阴性乳腺癌细胞周期抑制的脆弱性。
DOI：
10.1038/s41467-019-10743-7
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发表时间：
2019
影响因子：
16.6
通讯作者：
Zhang,Siyuan
中科院分区：
文献类型：
--
作者：
Ni,Yingjia;Schmidt,KeonR;Werner,BarnesA;Koenig,JennaK;Guldner,IanH;Schnepp,PatriciaM;Tan,Xuejuan;Jiang,Lan;Host,Misha;Sun,Longhua;Howe,ErinN;Wu,Junmin;Littlepage,LaurieE;Nakshatri,Harikrishna;Zhang,Siyuan
由于缺乏靶向分子驱动因子，三阴性乳腺癌（TNBC）是临床上最具挑战性的乳腺癌亚型。在这项研究中，我们揭示了在> 60%的TNBC中过表达的含有死亡效应结构域的DNA结合蛋白（DEDD）通过细胞质定位驱动不依赖于有丝分裂原的G1/S细胞周期转变。胞质可溶性DEDD的获得通过与热休克蛋白71 kDa 8（HSC 70）相互作用而增强细胞周期蛋白D1的表达。同时，DEDD与Rb家族蛋白相互作用，促进Rb家族蛋白的降解，DEDD过表达使TNBC细胞易受细胞周期抑制。TNBC患者已被排除在CDK 4/6抑制剂临床试验之外，因为TNBC中Rb丢失的频率较高。有趣的是，我们的研究表明，无论Rb状态如何，DEDD过表达的TNBC在体外和体内对CDK 4/6抑制剂和EGFR抑制剂的组合治疗表现出DEDD依赖性的脆弱性。因此，我们的研究为CDK 4/6抑制剂组合方案在TNBC患者中的临床应用提供了理论基础。
Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolicDEDDenhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently,DEDDinteracts with Rb family proteins and promotes their proteasome-mediated degradation.DEDDoverexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs withDEDDoverexpression exhibit aDEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC.