HER2/neu over-expression induces endothelial cell retraction

Over-expression of the HER2/neu (HER2) proto-oncogene in breast carcinoma i mparts an enhanced metastatic potential. Metastasis requires escape of the tumor cell from the vasculature into subjacent tissue, a transmigration eve nt across an endothelial cell (EC) monolayer, EC retraction has been report ed to precede transmigration in several tumor metastatic models, Using inta ct human iliac vein EC monolayers, we tested the abilities of MCF-7 breast cancer cells and HER cells, a transfected MCF-7 line over-expressing HER2, to induce EC retraction. We further analyzed whether HER2 signaling influen ced cancer cell-induced EC retraction. MCF-7 or HER cells were co-cultured onto mature EC monolayers. More HER than MCF-7 cells induced EC retraction (76 +/- 19% vs. 17 +/- 12%, p < 0.001) with resultant exposure of subendoth elial matrix (6.80 +/- 2.86% vs, 0.85 +/- 0.39%, p < 0.001), Blockade of HE R2 signaling using Herceptin(TM) nearly eliminated EC retraction (p < 0.01) , while stimulation of HER2 using heregulin-<beta>1-augmented EC retraction (p < 0.05). Further, there was no difference between cell lines in either the number of cells adhered or the strength of adherence to EC under sheer stress. These data suggest that HER2 signaling enhances metastasis in breas t cancer cells by inducing EC retraction, a process that appears to precede endothelial transmigration. (C) 2001 Wiley-Liss, Inc.