In another model of murine breast cancer, exogenous isthmin (a cell-secreted 60-kDa protein), was shown to bind to GRP78 on the surface of vascular endothelial cells and breast carcinoma 4T1 cells; in both types of the cells, the formed isthmin–GRP78 complex is internalized through clathrin-mediated endocytosis with subsequent induction of mitochondrial dysfunction and apoptosis [222]. This evidence concerns the gene ISM1 and breast carcinoma.