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Annals of Surgical Oncology

, Volume 14, Issue 10, pp 2971–2978 | Cite as

Mechanisms of HER2-Induced Endothelial Cell Retraction

  • W. Bradford Carter
  • Guilian Niu
  • Michael D. Ward
  • Gregory Small
  • Julianne E. Hahn
  • Barbara J. Muffly
Breast Oncology

Abstract

Background

HER2 overexpression imparts a metastatic advantage in breast cancer. We have shown that HER2 signaling in breast cancer cells induces adjacent endothelial cell (EC) retraction, disrupting endothelial integrity. Because endothelial integrity is dependent on the adherens junctions, we postulated that the mechanism of tumor cell-induced EC retraction involves dissociation of catenin proteins from vascular endothelial (VE) cadherin. In this study, we report a loss of VE-cadherin in tumor-associated EC. We also tested for a change of catenin dissociation from VE-cadherin by manipulating HER2 signaling in tumor cells.

Methods

We tested confluent monolayers of human EC for downregulation of VE cadherin and dissociation of catenins from VE cadherin after exposure to breast cancer cells or conditioned media. Using immunoprecipitation, we quantitated the remaining complexed catenins to VE-cadherin in tumor-associated EC after different treatments to manipulate HER2 signaling.

Results

Treatment of EC with conditioned media from MCF-7 cells expressing HER2 induced a loss of VE-cadherin expression, and time-dependent dissociation of catenins from VE cadherin. Catenin dissociation from VE-cadherin was enhanced by Heregulin β1 (P < .05) stimulation and decreased by trastuzumab (P < .05) blockade of HER2 signaling in cancer cells. An increase in EC phosphoSrc (Tyr 416) was seen by 8 hours.

Conclusions

Our data suggest that HER2 induction of EC retraction involves both down-regulation of VE-cadherin and dissociation of catenins. HER2 signaling appears to regulate this potential metastatic mechanism. Further, Src phosphorylation suggests that this pathway may be involved in this mechanism.

Keywords

Breast cancer HER2 VE-cadherin Catenin 

Notes

Acknowledgment

This research was supported by a grant from the Department of Defense, Breast Cancer Research Program, DAMD 17-00-1-0240, and the Jeffress Research Foundation, Jeffress Research Grant #J-460. Anita C. Bruce contributed editorial support.

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Copyright information

© Society of Surgical Oncology 2007

Authors and Affiliations

  • W. Bradford Carter
    • 1
  • Guilian Niu
    • 1
  • Michael D. Ward
    • 2
  • Gregory Small
    • 3
  • Julianne E. Hahn
    • 3
  • Barbara J. Muffly
    • 1
  1. 1.Don & Erika Wallace Comprehensive Breast Program at H. Lee Moffitt Cancer Center and Research Institute and Department of Interdisciplinary OncologyUniversity of South FloridaTampaUSA
  2. 2.Department of Microbiology/Immunology and Cell BiologyEastern Virginia Medical SchoolNorfolkUSA
  3. 3.Division of Surgical OncologyUniversity of MarylandBaltimoreUSA

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