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

• DOI: 10.7554/elife.81288
• Publication Date: 2023-01-10T13:00:13Z
• Authors: 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
• Keywords: caveolin-2; 0301 basic medicine; caveolin-1; QH301-705.5; Carcinogenesis; Science; Triple Negative Breast Neoplasms; Mice; 03 medical and health sciences; Humans; Animals; Stromal Interaction Molecule 1; Biology (General); Cancer Biology; Q; Cell Membrane; R; EHD2; 3. Good health; Cell Transformation, Neoplastic; triple negative breast cancer; caveolae; Medicine; Calcium; Carrier Proteins; SOCE

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.