Anti-RhoA and anti-RhoC siRNAs inhibit the proliferation and invasiveness of MDA-MB-231 breast cancer cells in vitro and in vivo

Mol Ther. 2005 Feb;11(2):267-74. doi: 10.1016/j.ymthe.2004.08.029.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Collagen
  • Cytoskeletal Proteins / metabolism
  • Down-Regulation / genetics
  • Drug Combinations
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Laminin
  • Mice
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / prevention & control
  • Neovascularization, Pathologic
  • Proteoglycans
  • Pyridines / pharmacology
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism*
  • Trans-Activators / metabolism
  • Transfection
  • beta Catenin
  • ras Proteins
  • rho GTP-Binding Proteins / deficiency*
  • rho GTP-Binding Proteins / genetics*
  • rho GTP-Binding Proteins / metabolism
  • rhoA GTP-Binding Protein / deficiency*
  • rhoA GTP-Binding Protein / genetics*
  • rhoA GTP-Binding Protein / metabolism
  • rhoC GTP-Binding Protein

Substances

  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • Drug Combinations
  • Enzyme Inhibitors
  • Laminin
  • Proteoglycans
  • Pyridines
  • RNA, Messenger
  • RNA, Small Interfering
  • Trans-Activators
  • beta Catenin
  • matrigel
  • Collagen
  • cerivastatin
  • RHOC protein, human
  • Rhoc protein, mouse
  • ras Proteins
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein
  • rhoC GTP-Binding Protein