The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGFβ signaling in triple-negative breast cancer

  1. Zane A Gibbs
  2. Luis Reza
  3. Chun-chun Cheng
  4. Jill Westcott
  5. Kathleen McGlynn
  6. Angelique Whitehurst  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States

Abstract

Cancer/testis (CT) antigens are proteins whose expression is normally restricted to germ cells yet aberrantly activated in tumors, where their functions remain relatively cryptic. Here we report that ZNF165, a CT antigen frequently expressed in triple-negative breast cancer (TNBC), associates with SMAD3 to modulate transcription of transforming growth factor β (TGFβ)-dependent genes and thereby promote growth and survival of human TNBC cells. In addition, we identify the KRAB zinc finger protein, ZNF446, and its associated tripartite motif protein, TRIM27, as obligate components of the ZNF165-SMAD3 complex that also support tumor cell viability. Importantly, we find that TRIM27 alone is necessary for ZNF165 transcriptional activity and is required for TNBC tumor growth in vivo using an orthotopic xenograft model in immunocompromised mice. Our findings indicate that aberrant expression of a testis-specific transcription factor is sufficient to co-opt somatic transcriptional machinery to drive a pro-tumorigenic gene expression program in TNBC.

Data availability

Data have been submitted under GEO access code GSE130364.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Zane A Gibbs

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0294-1878
  2. Luis Reza

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chun-chun Cheng

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jill Westcott

    Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kathleen McGlynn

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Angelique Whitehurst

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    angelique.whitehurst@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9505-0240

Funding

National Cancer Institute (5R01CA196905)

  • Zane A Gibbs
  • Luis Reza
  • Chun-chun Cheng
  • Angelique Whitehurst

National Institute of General Medical Sciences (5T32GM007062)

  • Zane A Gibbs

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (2016-101795) of UT-Southwestern. All surgery was performed under anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Joaquín M Espinosa, University of Colorado Anschutz Medical Campus, United States

Publication history

  1. Received: April 8, 2020
  2. Accepted: June 9, 2020
  3. Accepted Manuscript published: June 9, 2020 (version 1)
  4. Version of Record published: June 18, 2020 (version 2)

Copyright

© 2020, Gibbs et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Zane A Gibbs
  2. Luis Reza
  3. Chun-chun Cheng
  4. Jill Westcott
  5. Kathleen McGlynn
  6. Angelique Whitehurst
(2020)
The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGFβ signaling in triple-negative breast cancer
eLife 9:e57679.
https://doi.org/10.7554/eLife.57679

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