Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
Timothy A Bielecki
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
Bhopal C Mohapatra
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, United States; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, United States
Namista Islam
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States; Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, United States
Insha Mushtaq
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States; Department of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, United States
Aaqib M Bhat
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States; Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, United States
Sameer Mirza
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, United States
Sukanya Chakraborty
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States; Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, United States
Mohsin Raza
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, United States
Matthew D Storck
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
Michael S Toss
Department of Histopathology, Nottingham University Hospital NHS Trust, City Hospital Campus, Nottingham, United Kingdom
Jane L Meza
Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, United States; Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, United States
Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, United States
Donald W Coulter
Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, United States; Department of Pediatrics, University of Nebraska Medical Center, Omaha, United States
Emad A Rakha
Department of Histopathology, Nottingham University Hospital NHS Trust, City Hospital Campus, Nottingham, United Kingdom
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, United States; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, United States
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States; Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, United States; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, United States; Department of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, United States
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.
