EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry
- University of Nebraska Medical Center, United States
- Nottingham University Hospitals NHS Trust, United Kingdom
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
Wallace B Thoreson
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.
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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