Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer

Yingjia Ni, Keon R. Schmidt, Barnes A. Werner, Jenna K. Koenig, Ian H. Guldner, Patricia M. Schnepp, Xuejuan Tan, Lan Jiang, Misha Host, Longhua Sun, Erin N. Howe, Junmin Wu, Laurie E. Littlepage, Harikrishna Nakshatri and Siyuan Zhang ()
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Yingjia Ni: University of Notre Dame
Keon R. Schmidt: University of Notre Dame
Barnes A. Werner: University of Notre Dame
Jenna K. Koenig: University of Notre Dame
Ian H. Guldner: University of Notre Dame
Patricia M. Schnepp: University of Notre Dame
Xuejuan Tan: University of Notre Dame
Lan Jiang: University of Notre Dame
Misha Host: University of Notre Dame
Longhua Sun: University of Notre Dame
Erin N. Howe: University of Notre Dame
Junmin Wu: University of Notre Dame
Laurie E. Littlepage: University of Notre Dame
Harikrishna Nakshatri: Indiana University Melvin and Bren Simon Cancer Center
Siyuan Zhang: University of Notre Dame

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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 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.

Date: 2019
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DOI: 10.1038/s41467-019-10743-7

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