Inhibition of breast and ovarian tumor growth through multiple signaling pathways by using retrovirus-mediated small interfering RNA against Her-2/neu gene expression.
The Her-2/neu oncogene is overexpressed in approximately 30% of breast and ovarian cancer cases and often indicates a poor prognosis. Therapeutic agents against Her-2/neu have been intensively sought over the past decade. Here we show that small interfering RNA (siRNA) can silence the expression of Her-2/neu in models of human breast or ovarian cancer through retrovirus-mediated transfer of an siRNA against Her-2/neu. Cells infected with retrovirus expressing anti-Her-2/neu siRNA exhibit slower proliferation, increased apoptosis, increased G0/G1 arrest, and decreased tumor growth. Changes in cell cycle-associated factors included decreased levels of phosphatidylinositol 3-kinase, pAkt, and cyclin D1 and increased levels of p27 and phosphorylated retinoblastoma protein. Knockdown of Her-2/neu expression by siRNA is also associated with increased expression of the anti-angiogenic factor thrombospondin-1 and decreased expression of the pro-angiogenic vascular endothelial growth factor, suggesting that Her-2/neu stimulates tumor growth at least in part by regulating angiogenesis. siRNA-mediated gene silencing of Her-2/neu and increasing the expression of thrombospondin-1 may be a useful therapeutic strategy for Her-2/neu-over-expressing breast or ovarian cancer.
Yang
Gong
G
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4095, USA.
Cai
Kathy Qi
KQ
Thompson-Lanza
Jennifer A
JA
Bast
Robert C
RC
Liu
Jinsong
J
D017209:Apoptosis; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D018734:Genes, erbB-2; D005822:Genetic Vectors; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D034741:RNA, Small Interfering / Q000235:genetics* / Q000494:pharmacology; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A