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J. Biol. Chem., Vol. 279, Issue 22, 23773-23781, May 28, 2004

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The C Terminus of c-Src Inhibits Breast Tumor Cell Growth by a Kinase-independent Mechanism^*

Rumey C. Ishizawar, David A. Tice¶, Themistoclis Karaoli, and Sarah J. Parsons||

From the Department of Microbiology and Cancer Center, University of Virginia Health Services, Charlottesville, Virginia 22908 and ^¶MedImmune, Inc., Gaithersburg, Maryland 20878

Overexpression or increased activity of cellular Src (c-Src) is frequently detected in human breast cancer, implicating involvement of c-Src in the etiology of breast carcinomas. Curiously, overexpression of c-Src in tissue culture cells results in a weakly or non-transforming phenotype, indicating that it alone is not sufficient for oncogenesis. However, the protein has been demonstrated to potentiate mitogenic signals from transmembrane receptors. This report investigates the requirement for c-Src in breast cancer as a transducer and integrator of anchorage-dependent and -independent growth signals by utilizing the Src family pharmacological inhibitors, PP1 and PP2, or stable overexpression of the catalytically inactive c-Src mutant (K^- c-Src). Both methods of inhibiting endogenous c-Src diminished formation of soft agar colonies and tumors in nude mice. The majority of the dominant-negative activity of K^- c-Src was mapped to the Src homology 2 (SH2) domain and C-terminal half of the molecule, but not to the Unique domain, Src homology 3 (SH3) domain, or the N-terminal half of K^- c-Src. Further analysis of the C terminus revealed that its ability to inhibit growth localized to the N-terminal lobe (N-lobe) of the catalytic region. These results underscore the requirement for c-Src to maintain the oncogenic phenotype of breast cancer cells and suggest that c-Src may be manipulated to inhibit cell growth by the direct disruption of its catalytic activity or the introduction of either the SH2 domain or the N-lobe of K^- c-Src.

Received for publication, November 12, 2003 , and in revised form, March 17, 2004.

^* This work was supported by Department of Health and Human Services Grants CA3948 and CA71449 (to S. J. P.), Council for Tobacco Research Grant 4621 (to S. J. P.), and Department of Defense Grants DAMD 17-96-1-6126 (to D. A. T.) and DAMD 17-00-1-0487 (to R. C. I.). 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.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Box 800734, Dept. of Microbiology and Cancer Center, University of Virginia Health Services, Charlottesville, VA 22908. Tel.: 434-924-2352; Fax: 434-982-0689; E-mail: sap{at}virginia.edu.

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