PT  - JOURNAL ARTICLE
AU  - Haitao Luan
AU  - Timothy A. Bielecki
AU  - Bhopal C. Mohapatra
AU  - Namista Islam
AU  - Insha Mushtaq
AU  - Aaqib M. Bhat
AU  - Sameer Mirza
AU  - Sukanya Chakraborty
AU  - Mohsin Raza
AU  - Matthew D. Storck
AU  - Jane L. Meza
AU  - Wallace B. Thoreson
AU  - Donald W. Coulter
AU  - Emad A. Rakha
AU  - Vimla Band
AU  - Hamid Band
TI  - EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry
AID  - 10.1101/2022.06.21.497035
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.21.497035
4099  - http://biorxiv.org/content/early/2022/06/25/2022.06.21.497035.short
4100  - http://biorxiv.org/content/early/2022/06/25/2022.06.21.497035.full
AB  - 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 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. ShRNA knockdown and CRISPR-Cas9 knockout of EHD2, together 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.Competing Interest StatementDr. H. Band and Dr. V. Band received funding from Nimbus Therapeutics for an unrelated project.