HER2 Regulation of Angiopoietin-2: A Mechanistic Factor in Metastasis

摘要

HER2 overexpression is a poor prognostic indicator in breast cancer. HER2 amplification is associated with early tumor dissemination, rapid tumor progression, and increased invasiveness, implying that HER2 has a significant role in the metastatic phenotype. We have demonstrated that two key steps in the metastatic process, angioinvasion and transendothelial migration, are augmented by HER2 expression, and we have linked Angiopoietin-2, a vascular destabilizing protein, to expression of HER2 (1). The objective of this research is to determine if the metastatic advantage of HER2 expressing cancer cells is imparted by Angiopoietin-2 production, and further to determine if overexpression of HER2 up-regulates Angiopoietin-2 expression. The scope of this research was to test: 1) angioinvasion using an in vitro microvessel dismantling assay and 2) endothelial cell retraction, a key step in tumor-cell transendothelial migration. We tested HER2 amplified breast cancer cell production of Angiopoietin-2, using blockade or stimulation of HER2 signaling. To determine if Angiopoietin-2 modulates the metastatic steps in question, we applied Angiopoietin-2 directly, or sequestered Angiopoietin-2 in these models. Breast cancer specimens were also tested for correlation of expression of HER2 and Angiopoietin-2. Further, we identified mechanistic steps in HER2 regulation of Angiopoietin-2 in breast cancer cells. Lastly, we demonstrated that the mechanism of HER2 amplified breast cancer cell-induction of endothelial cell retraction involves downregulation of VE cadherin and dissociation of catenin proteins from VE cadherin. This process releases the adherins junctions of the endothelial monolayer, thereby disrupting endothelial integrity.