This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jallal, H. Articles by Rabbani, S. A. Search for Related Content PubMed PubMed Citation Articles by Jallal, H. Articles by Rabbani, S. A.

A Src/Abl Kinase Inhibitor, SKI-606, Blocks Breast Cancer Invasion, Growth, and Metastasis In vitro and In vivo

¹ Department of Medicine and Oncology, McGill University Health Center, Montreal, Quebec, Canada and ² Department of Oncology, Wyeth Research, Pearl River, New York

Requests for reprints: Shafaat A. Rabbani, Department of Medicine and Oncology, McGill University Health Center, 687 Pine Avenue West, Room H4.61, Montreal, Quebec, Canada H3A 1A1. Phone: 514-843-1632; Fax: 514-843-1712; E-mail: shafaat.rabbani{at}mcgill.ca.

The central role of Src in the development of several malignancies, including breast cancer, and the accumulating evidence of its interaction with receptor tyrosine kinases, integrins, and steroid receptors have identified it as an attractive therapeutic target. In the current study, we have evaluated the effect of a Src/Abl kinase inhibitor, SKI-606, on breast cancer growth, migration, invasion, and metastasis. Treatment of human breast cancer cells MDA-MB-231 with SKI-606 caused a marked inhibition of cell proliferation, invasion, and migration by inhibiting mitogen-activated protein kinase and Akt phosphorylation. For in vivo studies, MDA-MB-231 cells transfected with the plasmid encoding green fluorescent protein (GFP; MDA-MB-231-GFP) were inoculated into the mammary fat pads of female BALB/c nu/nu mice. Once tumor volume reached 30 to 50 mm³, animals were randomized and treated with vehicle alone or 150 mg/kg SKI-606 by daily oral gavage. Experimental animals receiving SKI-606 developed tumors of significantly smaller volume (45–54%) compared with control animals receiving vehicle alone. Analysis of lungs, liver, and spleen of these animals showed a significant decrease in GFP-positive tumor metastasis in animals receiving SKI-606 at a dose that was well tolerated. Western blot analysis and immunohistochemical analysis of primary tumors showed that these effects were due to the ability of SKI-606 to block tumor cell proliferation, angiogenesis, growth factor expression, and inhibition of Src-mediated signaling pathways in vivo. Together, the results from these studies provide compelling evidence for the role of Src inhibitors as therapeutic agents for blocking breast cancer growth and metastasis. [Cancer Res 2007;67(4):1580–8]

This article has been cited by other articles:

				R. S. Finn Targeting Src in breast cancer Ann. Onc., May 16, 2008; (2008) mdn291v1. [Abstract] [Full Text] [PDF]

				A. Vultur, R. Buettner, C. Kowolik, W. Liang, D. Smith, F. Boschelli, and R. Jove SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells Mol. Cancer Ther., May 1, 2008; 7(5): 1185 - 1194. [Abstract] [Full Text] [PDF]

				W. Yan, B. Bentley, and R. Shao Distinct Angiogenic Mediators Are Required for Basic Fibroblast Growth Factor- and Vascular Endothelial Growth Factor-induced Angiogenesis: The Role of Cytoplasmic Tyrosine Kinase c-Abl in Tumor Angiogenesis Mol. Biol. Cell, May 1, 2008; 19(5): 2278 - 2288. [Abstract] [Full Text] [PDF]

				C. R. Acharya, D. S. Hsu, C. K. Anders, A. Anguiano, K. H. Salter, K. S. Walters, R. C. Redman, S. A. Tuchman, C. A. Moylan, S. Mukherjee, et al. Gene Expression Signatures, Clinicopathological Features, and Individualized Therapy in Breast Cancer JAMA, April 2, 2008; 299(13): 1574 - 1587. [Abstract] [Full Text] [PDF]

				Y.-X. Zhang, P. G. Knyazev, Y. V. Cheburkin, K. Sharma, Y. P. Knyazev, L. Orfi, I. Szabadkai, H. Daub, G. Keri, and A. Ullrich AXL Is a Potential Target for Therapeutic Intervention in Breast Cancer Progression Cancer Res., March 15, 2008; 68(6): 1905 - 1915. [Abstract] [Full Text] [PDF]

				S. Kopetz, A. N. Shah, and G. E. Gallick Src Continues Aging: Current and Future Clinical Directions Clin. Cancer Res., December 15, 2007; 13(24): 7232 - 7236. [Abstract] [Full Text] [PDF]

				D. Schunke, P. Span, H. Ronneburg, A. Dittmer, M. Vetter, H.-J. Holzhausen, E. Kantelhardt, S. Krenkel, V. Muller, F. C.G.J. Sweep, et al. Cyclooxygenase-2 Is a Target Gene of Rho GDP Dissociation Inhibitor {beta} in Breast Cancer Cells Cancer Res., November 15, 2007; 67(22): 10694 - 10702. [Abstract] [Full Text] [PDF]