Abstract
Overexpression of RhoA or RhoC in breast cancer indicates a poor prognosis, due to increased tumor cell proliferation and invasion and tumor-dependent angiogenesis. Until now, the strategy of blockage of the Rho-signaling pathway has used either GGTI or HMG-CoA reductase inhibitors, but they are not specific to RhoA or RhoC inhibition. In this study, a new approach with anti-RhoA and anti-RhoC siRNAs was used to inhibit specifically RhoA or RhoC synthesis. Two transfections of either RhoA or RhoC siRNA (8.5 nM) into MDA-MB-231 human breast cancer cells or HMEC-1 endothelial cells induced extensive degradation of the target mRNA and led to a dramatic decrease in synthesis of the corresponding protein. In vitro, these siRNAs inhibited cell proliferation and invasion more effectively than conventional blockers of Rho cell signaling. Finally, in a nude mouse model, intratumoral injections of anti-RhoA siRNA (100 microl at 85 nM) every 3 days for 20 days almost totally inhibited the growth and angiogenesis of xenografted MDA-MB-231 tumors. One may infer from these observations that specific inhibition of the Rho-signaling pathway with siRNAs represents a promising approach for the treatment of aggressive breast cancers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Breast Neoplasms / blood supply
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cell Proliferation
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Collagen
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Cytoskeletal Proteins / metabolism
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Down-Regulation / genetics
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Drug Combinations
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic
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Humans
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Laminin
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Mice
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Neoplasm Invasiveness / genetics
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Neoplasm Invasiveness / prevention & control
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Neovascularization, Pathologic
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Proteoglycans
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Pyridines / pharmacology
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RNA Interference
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism*
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Trans-Activators / metabolism
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Transfection
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beta Catenin
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ras Proteins
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rho GTP-Binding Proteins / deficiency*
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rho GTP-Binding Proteins / genetics*
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rho GTP-Binding Proteins / metabolism
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rhoA GTP-Binding Protein / deficiency*
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rhoA GTP-Binding Protein / genetics*
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rhoA GTP-Binding Protein / metabolism
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rhoC GTP-Binding Protein
Substances
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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Drug Combinations
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Enzyme Inhibitors
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Laminin
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Proteoglycans
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Pyridines
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RNA, Messenger
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RNA, Small Interfering
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Trans-Activators
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beta Catenin
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matrigel
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Collagen
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cerivastatin
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RHOC protein, human
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Rhoc protein, mouse
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ras Proteins
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein
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rhoC GTP-Binding Protein