2. Academic Validation
  3. 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

  • Nat Commun. 2019 Jun 28;10(1):2860. doi: 10.1038/s41467-019-10743-7.
Yingjia Ni 1 2,  Keon R Schmidt 1 2,  Barnes A Werner 1 2,  Jenna K Koenig 1 2,  Ian H Guldner 1 2,  Patricia M Schnepp 1 2,  Xuejuan Tan 1 2,  Lan Jiang 1 2,  Misha Host 1 2,  Longhua Sun 1 2,  Erin N Howe 1 2,  Junmin Wu 2 3,  Laurie E Littlepage 2 3 4,  Harikrishna Nakshatri 4 5,  Siyuan Zhang 6 7 8 9
Affiliations

Affiliations

  • 1 Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA.
  • 2 Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, 46617, USA.
  • 3 Department of Chemistry and Biochemistry, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA.
  • 4 Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA.
  • 5 Departments of Surgery, Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
  • 6 Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA. szhang8@nd.edu.
  • 7 Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, 46617, USA. szhang8@nd.edu.
  • 8 Department of Chemistry and Biochemistry, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA. szhang8@nd.edu.
  • 9 Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA. szhang8@nd.edu.
PMID: 31253784 DOI: 10.1038/s41467-019-10743-7
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.

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