Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 28, 2019
- Source ID
- 10.1038/s41467-019-10743-7
Entities
People
- Barnes A. Werner
- Erin N Howe
- Harikrishna Nakshatri
- Ian H. Guldner
- Jenna K Koenig
- Junmin Wu
- Keon R. Schmidt
- Lan Jiang
- Laurie E Littlepage
- Longhua Sun
- Misha Host
- Patricia M Schnepp
- Siyuan Zhang
- Xuejuan Tan
- Yingjia Ni
Organizations
- National Cancer Institute
- United States Department of Defense