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NEDD9 Promotes Oncogenic Signaling in Mammary Tumor Development

Programs in ¹ Molecular and Translational Medicine and ² Immunology and ³ Women's Cancer, Fox Chase Cancer Center; ⁴ Department of Biochemistry, Drexel University School of Medicine, Philadelphia, Pennsylvania; ⁵ Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel; ⁶ Department of Molecular Biology and Medical Biotechnology, Russian State Medical University, Moscow, Russia; ⁷ Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and ⁸ Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia

Requests for reprints: Erica A. Golemis, Program in Molecular and Translational Medicine, Fox Chase Cancer Center, W406, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-728-2860; Fax: 215-728-3616; E-mail: EA_Golemis{at}fccc.edu.

Key Words: HEF1 • mammary • NEDD9

In the past 3 years, altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has emerged as contributing to cancer metastasis in multiple cancer types. However, whereas some studies have identified elevated NEDD9 expression as prometastatic, other work has suggested a negative role in tumor progression. We here show that the Nedd9-null genetic background significantly limits mammary tumor initiation in the MMTV-polyoma virus middle T genetic model. Action of NEDD9 is tumor cell intrinsic, with immune cell infiltration, stroma, and angiogenesis unaffected. The majority of the late-appearing mammary tumors of MMTV-polyoma virus middle T;Nedd9^–/– mice are characterized by depressed activation of proteins including AKT, Src, FAK, and extracellular signal-regulated kinase, emphasizing an important role of NEDD9 as a scaffolding protein for these prooncogenic proteins. Analysis of cells derived from primary Nedd9^+/+ and Nedd9^–/– tumors showed persistently reduced FAK activation, attachment, and migration, consistent with a role for NEDD9 activation of FAK in promoting tumor aggressiveness. This study provides the first in vivo evidence of a role for NEDD9 in breast cancer progression and suggests that NEDD9 expression may provide a biomarker for tumor aggressiveness. [Cancer Res 2009;69(18):7198–206]