P5-02-04: Disruption of Endothelial Cells Barrier Integrity by Invasive Breast Cancer Cells.

Abstract

Abstract Despite its critical role in cancer metastasis the molecular mechanisms regulating breast cancer cells transendothelial migration are poorly understood, but clearly depend on the invasive capacity of tumor cells and their ability to breach the endothelial cell barrier. Vascular endothelial-cadherin (VE-cadherin) is found specifically in the endothelial cell adherens junction and has been implicated in playing a fundamental role in controlling the transport across the endothelial barrier. Tyrosine phosphorylation of VE-cadherin has been implicated in the disruption of endothelial cells adherens junctions and diapedesis of metastatic cancer cells. We tested this hypothesis that interaction of breast cancer cells with endothelial cells initiates the signal transductions that disrupt the endothelium barrier integrity. Our studies demonstrated that the attachment of MDA-MB-231 human breast cancer cells to Human Umbilical Vein Endothelial Cells (HUVECs) leads to tyrosine phosphorylation of VE-cadherin and the formation of gaps between endothelial cells. These were accompanied by activation of two tyrosine kinases, Src and proline rich tyrosine kinase (Pyk-2). In addition, immunoprecipitation studies indicated that the endothelial cells adherens junction structure was disrupted through MDA-MB-231-induced dissociation of VE-cadherin and β-catenin complex. Activation of RhoA and HRas by over expression of constitutively active forms of the genes leads to tyrosine phosphorylation of VE-cadherin and Pyk-2 in HUVECs. Over expression of dominant negative forms of RhoA, HRas, Raf and ERK2 but not Rac1 and Cdc42 attenuated breast cancer cell-induced tyrosine phosphorylation of VE-cadherin and Pyk-2 in HUVECs. Indicating that breast cancer cell-induced VE-cadherin tyrosine phosphorylation and disruption of adherens junction in endothelial cells is mediated by RhoA and HRas\Raf\MEK\ERK signaling cascade. Understanding the precise molecular mechanisms that facilitate breast cancer cells transendothelial migration could develop novel therapeutic strategies targeting cancer cell metastasis by improving the protective role of endothelial cells. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-02-04.