Background: The human epidermal growth factor receptor 2 protein (HER2) signaling in breast cancer imparts a metastatic advantage to the cell, likely by regulating gene expression. The HER2 signaling up-regulates angiopoietin-2 (Ang-2), which disrupts endothelial cell (EC) adherens junctions. We postulated that HER2 signaling may facilitate angioinvasion by disrupting microvessel integrity.
Methods: Rat microvessels, embedded in collagen, were grown into capillary networks and cocultured with MCF-7 or HER2 overexpressing MCF-7 (HER) to test for microvessel breakdown. We quantitated this effect by determining the cumulative length of intact microvessels. Other experiments used Herceptin- or heregulin beta 1-pretreated MCF-7 cells to modulate HER2 signaling, or soluble Tie-2/Fc receptor fusion protein (sTie2) to sequester tumor-cell released Ang-2.
Results: The MCF-7 cells induced a time-dependent loss of microvessel integrity. At 12 hours, HER cells induced a 90% reduction in cumulative length (P <.05). Pretreatment with Herceptin reduced whereas heregulin beta 1 augmented microvessel dismantling (P <.01). Sequestration of Ang-2 significantly, though not dramatically, reduced the MCF-7 cell induction of microvessel dismantling (P <.01).
Conclusions: We show that HER2 signaling in breast cancer cells leads to induction of microvessel dismantling, which may open a portal for angioinvasion. It appears that Ang-2 affects this mechanism, although other factors also function in microvessel dismantling.