University of Notre Dame
Browse

File(s) stored somewhere else

Please note: Linked content is NOT stored on University of Notre Dame and we can't guarantee its availability, quality, security or accept any liability.

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

journal contribution
posted on 2020-04-08, 00:00 authored by Barnes Werner, Erin Howe, Harikrishna Nakshtri, Ian Guldner, Jenna Koenig, Junmin Wu, Keon R. Schmidt, Lan Jiang, Laurie Littlepage, Longhua Sun, Misha Host, Patricia Schnepp, Siyua Zhang, Xuejuan Tan
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.

History

Date Modified

2020-04-08

Language

  • English

Alternate Identifier

4146701910|20411723

Publisher

Nature

Usage metrics

    Integrated Imaging Facility

    Categories

    No categories selected

    Keywords

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC