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

Article

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.

Attributes

Attribute NameValues
Creator
  • Keon R. Schmidt

  • Barnes Werner

  • Jenna Koenig

  • Ian Guldner

  • Patricia Schnepp

  • Xuejuan Tan

  • Lan Jiang

  • Misha Host

  • Longhua Sun

  • Erin Howe

  • Junmin Wu

  • Laurie Littlepage

  • Harikrishna Nakshtri

  • Siyua Zhang

Journal or Work Title
  • Nature Communications

Volume
  • 10

Issue
  • 1

First Page
  • 1

Last Page
  • 15

ISSN
  • 20411723

ISBN
  • 4146701910

Publication Date
  • 2019-07

Subject
  • Histology

Publisher
  • Nature

Date Created
  • 2020-04-08

Language
  • English

Departments and Units
Record Visibility Public
Content License
  • All rights reserved

Digital Object Identifier

doi:10.1038/s41467-019-10743-7

This DOI is the best way to cite this article.