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

Yingjia Ni1,2, Keon R Schmidt1,2, Barnes A Werner1,2

  • 1Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA.

Nature Communications
|June 30, 2019
PubMed

Insights

Death Effector Domain-containing DNA-binding protein (DEDD) drives triple-negative breast cancer (TNBC) cell cycle progression. DEDD overexpression creates vulnerability to combined CDK4/6 and EGFR inhibitor therapy in TNBC, regardless of Rb status.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Triple-negative breast cancer (TNBC) lacks targeted therapies, making it clinically challenging.
  • Overexpression of Death Effector Domain-containing DNA-binding protein (DEDD) is observed in over 60% of TNBC cases.

Purpose of the Study:

  • To investigate the role of DEDD in TNBC pathogenesis.
  • To explore DEDD's mechanism in cell cycle regulation.
  • To assess the therapeutic potential of targeting DEDD in TNBC.

Main Methods:

  • Investigated DEDD's role in cell cycle transition via cytoplasmic localization.
  • Examined DEDD's interaction with HSC70 to enhance cyclin D1 expression.
  • Analyzed DEDD's interaction with Rb family proteins and its effect on proteasomal degradation.
  • Evaluated the efficacy of combinatorial CDK4/6 and EGFR inhibitors in DEDD-overexpressing TNBC models.

Main Results:

  • DEDD drives a mitogen-independent G1/S cell cycle transition.
  • Cytosolic DEDD enhances cyclin D1 expression via HSC70 interaction.
  • DEDD promotes proteasome-mediated degradation of Rb family proteins.
  • DEDD overexpression sensitizes TNBC cells to cell cycle inhibition.
  • TNBCs with DEDD overexpression show vulnerability to combined CDK4/6 and EGFR inhibitors, irrespective of Rb status.

Conclusions:

  • DEDD is a key driver of cell cycle progression in TNBC.
  • DEDD overexpression creates a therapeutic vulnerability in TNBC.
  • Combined CDK4/6 and EGFR inhibition is a promising therapeutic strategy for DEDD-overexpressing TNBC.

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