HER2 signaling--induced microvessel dismantling.
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.
Carter
W B
WB
Division of Surgical Oncology, University of Maryland, Baltimore, 21201, USA.
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000818:Animals; D001943:Breast Neoplasms; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008833:Microcirculation / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D066247:Receptor, ErbB-4; D042787:Receptor, TIE-2; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467629:Angpt1 protein, rat; D008562:Membrane Glycoproteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D066247:Receptor, ErbB-4; D042787:Receptor, TIE-2