Ni, YingjiaSchmidt, Keon R.Werner, Barnes A.Koenig, Jenna K.Guldner, Ian H.Schnepp, Patricia M.Tan, XuejuanJiang, LanHost, MishaSun, LonghuaHowe, Erin N.Wu, JunminLittlepage, Laurie E.Nakshatri, HarikrishnaZhang, Siyuan2019-09-052019-09-052019-06-28Ni, Y., Schmidt, K. R., Werner, B. A., Koenig, J. K., Guldner, I. H., Schnepp, P. M., … Zhang, S. (2019). Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer. Nature communications, 10(1), 2860. doi:10.1038/s41467-019-10743-7https://hdl.handle.net/1805/20797Lacking 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 cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression 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 with DEDD overexpression exhibit a DEDD-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.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesCancerCell biologyDrug discoveryBiomarkersOncologyArticle