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

Haitao Luan, Timothy A. Bielecki, Bhopal C. Mohapatra, Namista Islam, Insha Mushtaq, Aaqib M. Bhat, Sameer Mirza, Sukanya Chakraborty, Mohsin Raza, Matthew D. Storck, Michael S. Toss, Jane L. Meza, Wallace B. Thoreson, Donald W. Coulter, Emad A. Rakha, Vimla Band, Hamid Band

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Article numbere81288
JournaleLife
Volume12
DOIs
Publication statusPublished - 2023
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology

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