Role of Activated Rac1/Cdc42 in Mediating Endothelial Cell Proliferation and Tumor Angiogenesis in Breast Cancer
Open Access
- 4 June 2013
- journal article
- retracted article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (6), e66275
- https://doi.org/10.1371/journal.pone.0066275
Abstract
Angiogenesis is a well-established target in anti-cancer therapy. Although vascular endothelial growth factor (VEGF)-mediated angiogenesis apparently requires the Rho GTPases Rac1 and Cdc42, the relevant mechanisms are unclear. Here, we determined that activated Rac1/Cdc42 in MCF-7 breast cancer cells could decrease p53 protein levels and increase VEGF secretion to promote proliferation and tube formation of human umbilical vein endothelial cells (HUVECs). However, these effects are reversed after ubiquitin-proteasome breakage. In exploring potential mechanisms for this relationship, we confirmed that activated Rac1/Cdc42 could enhance p53 protein ubiquitination and weaken p53 protein stability to increase VEGF expression. Furthermore, in a xenograft model using nude mice that stably express active Rac1/Cdc42 protein, active Rac1/Cdc42 decreased p53 levels and increased VEGF expression. Additionally, tumor angiogenesis was inhibited, and p53 protein levels were augmented, by intratumoral injection of the ubiquitin-proteasome inhibitor MG132. Finally in 339 human breast cancer tissues, our analyses indicated that Rac1/Cdc42 expression was related to advanced TNM staging, high proliferation index, ER status, and positive invasive features. In particular, our data suggests that high Rac1/Cdc42 expression is correlated with low wt-p53 and high VEGF expression. We conclude that activated Rac1/Cdc42 is a vascular regulator of tumor angiogenesis and that it may reduce stability of the p53 protein to promote VEGF expression by enhancing p53 protein ubiquitin.Keywords
This publication has 33 references indexed in Scilit:
- Inhibition of endothelial cell proliferation by targeting Rac1 GTPase with small interference RNA in tumor cellsBiochemical and Biophysical Research Communications, 2004
- HER-2 Testing in Breast Cancer Using Parallel Tissue-Based MethodsJAMA, 2004
- Rho activity critically and selectively regulates endothelial cell organization during angiogenesisProceedings of the National Academy of Sciences of the United States of America, 2004
- Temporal and Spatial Modulation of Rho GTPases during in Vitro Formation of Capillary Vascular NetworkOnline Journal of Public Health Informatics, 2003
- Activated Cdc42 Sequesters c-Cbl and Prevents EGF Receptor DegradationCell, 2003
- Tumorigenesis and the angiogenic switchNature Reviews Cancer, 2003
- Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parametersBritish Journal of Cancer, 2002
- Central role of p53 on regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in mammary carcinoma.2001
- Rho GTPases as Modulators of the Estrogen Receptor Transcriptional ResponseOnline Journal of Public Health Informatics, 2001
- The von Hippel-Lindau Tumor Suppressor Gene Product Interacts with Sp1 To Repress Vascular Endothelial Growth Factor Promoter ActivityMolecular and Cellular Biology, 1997