HER2 signaling-induced microvessel dismantling

Background. The human epidermal growth factor receptor 2 protein (HER2) sig naling in breast cancer imparts a metastatic advantage to the cell, likely by regulating gene expression. The HER2 signaling upregulates angiopoietin- 2 (Ang-2), which disrupts endothelial cell (EC) adherens junctions. We post ulated that HER2 signaling may facilitate angioinvasion by disrupting micro vessel integrity. Methods. Rat microvessels, embedded in collagen, were grown into capillary networks and cocultured with MCF-7 or HER2 overexpressing MCF-7 (RER) to te st for microvessel breakdown. We quantitated this effect by determining the cumulative length of intact microvessels. Other experiments used Herceptin - or heregulin beta1-pretreated MCF-7 cells to modulate HER2 signaling, or soluble Tie-2/Fc receptor fusion protein (sTie2) to sequester tumor-cell re leased Ang-2. Results. The MCF-7 cells induced a time-dependent loss of microvessel integ rity. At 12 hours, HER cells induced a 90% reduction in cumulative length ( P < .05). Pretreatment with Herceptin reduced whereas heregulin <beta>1 aug mented microvessel dismantling (P < .01). Sequestration of Ang-2 significan tly, though not dramatically, reduced the MCF-7 cell induction of microvess el dismantling (P < .01). Conclusions. We show that HER2 signaling in breast cancer cells leads to in duction of microvessel dismantling, which may open a portal for angioinvasi on. It appears that Ang-2 affects this mechanism, although other factors al so junction in microvessel dismantling.