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
  • 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. [email protected].
  • 7. Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, 46617, USA. [email protected].
  • 8. Department of Chemistry and Biochemistry, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA. [email protected].
  • 9. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA. [email protected].
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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