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J. Biol. Chem., Vol. 283, Issue 2, 1008-1017, January 11, 2008

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IQGAP1 Stimulates Proliferation and Enhances Tumorigenesis of Human Breast Epithelial Cells^*

Lorraine Jadeski¹, Jennifer M. Mataraza¹², Ha-Won Jeong, Zhigang Li, and David B. Sacks³

From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115 and the Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada

The scaffold protein IQGAP1 integrates signaling pathways and participates in diverse cellular activities. IQGAP1 is overexpressed in a number of human solid neoplasms, but its functional role in tumorigenesis has not been previously evaluated. Here we report that IQGAP1 contributes to neoplastic transformation of human breast epithelial cells. The amount of IQGAP1 in breast carcinoma is greater than that in normal tissue, with highly metastatic breast epithelial cells expressing the highest levels. Overexpression of IQGAP1 enhances proliferation of MCF-7 breast epithelial cells. Reduction of endogenous IQGAP1 by RNA interference impairs both serum-dependent and anchorage-independent growth of MCF-7 cells. Consistent with these in vitro observations, immortalized MCF-7 cells overexpressing IQGAP1 form invasive tumors in immunocompromised mice, whereas tumors derived from MCF-7 cells with stable knockdown of IQGAP1 are smaller and less invasive. In vitro analysis with selected IQGAP1 mutant constructs and a chemical inhibitor suggests that actin, Cdc42/Rac1, and the mitogen-activated protein kinase pathway contribute to the mechanism by which IQGAP1 increases cell invasion. Collectively, our data reveal that IQGAP1 enhances mammary tumorigenesis, suggesting that it may be a target for therapeutic intervention.

Received for publication, October 11, 2007

^* This work was supported in part by a grant from the National Institutes of Health (to D. B. S.). 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.

¹ These authors contributed equally to this work.

² Present address: Organon Research Center, Cambridge, MA 02142.

³ To whom correspondence should be addressed: Brigham and Women's Hospital, Thorn 530, 75 Francis St. Boston, MA 02115. Tel.: 617-732-6627; Fax: 617-278-6921; E-mail: dsacks{at}rics.bwh.harvard.edu.

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