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J. Biol. Chem., Vol. 279, Issue 6, 4339-4345, February 6, 2004

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Inhibition of Breast and Ovarian Tumor Growth through Multiple Signaling Pathways by Using Retrovirus-mediated Small Interfering RNA against Her-2/neu Gene Expression^*

Gong Yang, Kathy Qi Cai, Jennifer A. Thompson-Lanza, Robert C. Bast, Jr., and Jinsong Liu¶

From the Departments of Pathology and Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4095

The Her-2/neu oncogene is overexpressed in 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.

Received for publication, October 10, 2003 , and in revised form, November 5, 2003.

^* This work is supported by Research Scholar Grant RSG-04-028-1-CCE from the American Cancer Society, by a Career Development Award (to J. L.) from The University of Texas M. D. Anderson Cancer Center Specialized Program of Research Excellence (SPORE) in Ovarian Cancer (Grant P50 CA83639) and project 1 (to R. C. B.) from the same SPORE. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Pathology, The University of Texas M. D. Anderson Cancer Center, Box 85, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-745-1102; Fax: 713-792-5529; E-mail: jliu{at}mdanderson.org.

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