Anti-RhoA and anti-RhoC siRNAs inhibit the proliferation and invasiveness of MDA-MB-231 breast cancer cells in vitro and in vivo.
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.
Pillé
J-Y
JY
Laboratoire de Recherche MERCI, EA 2122, Faculté de Médecine et Pharmacie, 76183 Rouen, France.
Denoyelle
C
C
Varet
J
J
Bertrand
J-R
JR
Soria
J
J
Opolon
P
P
Lu
H
H
Pritchard
L-L
LL
Vannier
J-P
JP
Malvy
C
C
Soria
C
C
Li
H
H
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000517:prevention & control; D009389:Neovascularization, Pathologic; D011509:Proteoglycans; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin; D018631:ras Proteins; D020741:rho GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D011509:Proteoglycans; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015534:Trans-Activators; D051176:beta Catenin; C059485:matrigel; D003094:Collagen; C086276:cerivastatin; C066690:RHOC protein, human; C512911:Rhoc protein, mouse; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein