EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry

Abstract

With nearly all cancer deaths a result of metastasis, elucidating novel pro-metastatic cellular adaptations could provide new therapeutic targets. Here, we show that overexpression of the EPS15-Homology Domain-containing 2 (EHD2) protein in a large subset of breast cancers (BCs), especially the triple-negative (TNBC) and HER2+ subtypes, correlates with shorter patient survival. The mRNAs for EHD2 and Caveolin-1/2, structural components of caveolae, show co-overexpression across breast tumors, predicting shorter survival in basal-like BC. EHD2 shRNA knockdown and CRISPR-Cas9 knockout with mouse Ehd2 rescue, in TNBC cell line models demonstrate a major positive role of EHD2 in promoting tumorigenesis and metastasis. Mechanistically, we link these roles of EHD2 to store-operated calcium entry (SOCE), with EHD2-dependent stabilization of plasma membrane caveolae ensuring high cell surface expression of the SOCE-linked calcium channel Orai1. The novel EHD2-SOCE oncogenic axis represents a potential therapeutic target in EHD2 and CAV1/2-overexpressing BC.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file.

Article and author information

Author details

  1. Haitao Luan

    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  2. Timothy A Bielecki

    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  3. Bhopal C Mohapatra

    Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  4. Namista Islam

    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  5. Insha Mushtaq

    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  6. Aaqib M Bhat

    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  7. Sameer Mirza

    Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  8. Sukanya Chakraborty

    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  9. Mohsin Raza

    Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  10. Matthew D Storck

    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  11. Michael S Toss

    Department of Histopathology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
    Competing interests
    No competing interests declared.
  12. Jane L Meza

    Departments of Biostatistics, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  13. Wallace B Thoreson

    Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7104-042X
  14. Donald W Coulter

    Department of Pediatrics, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  15. Emad A Rakha

    Department of Histopathology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
    Competing interests
    No competing interests declared.
  16. Vimla Band

    Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, United States
    For correspondence
    vband@unmc.edu
    Competing interests
    Vimla Band, received funding from Nimbus Therapeutics for an unrelated project..
  17. Hamid Band

    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
    For correspondence
    hband@unmc.edu
    Competing interests
    Hamid Band, received funding from Nimbus Therapeutics for an unrelated project..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4996-9002

Funding

Department of Defence (W81XWH-17-1-0616 and W81XWH-20-1-0058)

  • Hamid Band

Department of Defence (W81XWH-20-1-0546)

  • Vimla Band

National Institutes of Health (R21CA241055 and R03CA253193)

  • Vimla Band

Fred and Pamela Buffett Cancer Center (Pilot grant)

  • Vimla Band

Fred and Pamela Buffett Cancer Center (Pilot grant)

  • Hamid Band

University of Nebraska Medical Center (Graduate Student Fellowships)

  • Timothy A Bielecki

University of Nebraska Medical Center (Graduate Student Fellowships)

  • Aaqib M Bhat

University of Nebraska Medical Center (Graduate Student Fellowships)

  • Sukanya Chakraborty

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

Ethics

Animal experimentation: All mouse xenograft and treatment studies were pre-approved by the UNMC Institutional Animal Care and Use Committee (IACUC) under the IACUC protocol number 19-115-10-FC and conducted strictly according to the pre-approved procedures, in compliance with Federal and State guidelines.

Human subjects: Human tissues were collected and processed at the Nottingham University Hospital, United Kingdom. This study was approved by the Yorkshire & The Humber-Leeds East Research Ethics Committee (REC reference: 19/YH/0293) under the IRAS Project ID: 266925. Informed consent was obtained from all individuals prior to surgery for the use of their tissue materials in research. All samples were properly coded and anonymized in accordance with the approved protocols.

Reviewing Editor

  1. Jonathan A Cooper, Fred Hutchinson Cancer Center, United States

Version history

  1. Received: June 22, 2022
  2. Preprint posted: June 25, 2022 (view preprint)
  3. Accepted: January 10, 2023
  4. Accepted Manuscript published: January 10, 2023 (version 1)
  5. Version of Record published: March 6, 2023 (version 2)

Copyright

© 2023, Luan 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. Haitao Luan
  2. Timothy A Bielecki
  3. Bhopal C Mohapatra
  4. Namista Islam
  5. Insha Mushtaq
  6. Aaqib M Bhat
  7. Sameer Mirza
  8. Sukanya Chakraborty
  9. Mohsin Raza
  10. Matthew D Storck
  11. Michael S Toss
  12. Jane L Meza
  13. Wallace B Thoreson
  14. Donald W Coulter
  15. Emad A Rakha
  16. Vimla Band
  17. Hamid Band
(2023)
EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry
eLife 12:e81288.
https://doi.org/10.7554/eLife.81288

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