Abstract The multistep dynamic process of metastasis is the primary cause of breast cancer deaths. C‐terminal Eps15‐homology domain‐containing protein 1 (EHD1), a translocator associated with endocytic recycling, has been implicated in various oncogenic processes. However, the precise molecular mechanisms of EHD1‐induced breast cancer metastases remain largely unexplored. Here we found that the upregulation of EHD1 in breast cancer was positively associated with distant lymph node metastasis in patients. Meanwhile, EHD1 promoted epithelial‐mesenchymal transition (EMT), invasion, and metastasis of breast cancer cells in both two‐dimensional (2D) and three‐dimensional (3D) culture models in vitro, as well as in vivo. Remarkably, EHD1 can activate the AKT–mTOR pathway to upregulate the protein expression of hypoxia‐inducible factor 2α (HIF2α) under normoxic conditions and subsequently enhance the invasive and metastatic breast cancer. Our findings indicated EHD1 as a new regulator of HIF2α and a potential therapeutic target for inhibiting breast cancer metastasis.

EHD1 promotes breast cancer metastasis through upregulating HIF2a expression via activating mTOR pathway