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 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 Statement
Dr. H. Band and Dr. V. Band received funding from Nimbus Therapeutics for an unrelated project.
Footnotes
↵* Co-First Authors
Financial Supports: This research was funded by: the Department of Defense grants W81XWH-17-1-0616 and W81XWH-20-1-0058 to HB and W81XWH-20-1-0546 to VB; the NIH grants R21CA241055 and R03CA253193 to VB; pilot grants from the Fred & Pamela Buffett Cancer Center (HB & VB); the Raphael Bonita Memorial Fund; and support to UNMC core facilities from the NCI Cancer Center Support Grant (P30CA036727) awarded to Fred & Pamela Buffett Cancer Center and from the Nebraska Research Initiative. TAB, AMB and SC received University of Nebraska Medical Center Graduate Student Fellowships.
Conflict of interest disclosure statement: Dr. H. Band and Dr. V. Band received funding from Nimbus Therapeutics for an unrelated project.
