title: Role of activated Rac1/Cdc42 in mediating endothelial cell proliferation and tumor angiogenesis in breast cancer.
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.
authors.affiliation: Department of Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Yan
authors.initials: Y
authors.lastname: Xue
authors.forename: Wenchao
authors.initials: W
authors.lastname: Liu
authors.forename: Caixia
authors.initials: C
authors.lastname: Yue
authors.forename: Feng
authors.initials: F
authors.lastname: Bi
authors.forename: Junqing
authors.initials: J
authors.lastname: Xu
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Cuiping
authors.initials: C
authors.lastname: Zhong
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D061986:MCF-7 Cells; D051379:Mice; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D007976:Leupeptins; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde