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Izumchenko E , Singh MK , Plotnikova OV , Tikhmyanova N , Little JL , Serebriiskii IG , Seo S , Kurokawa M , Egleston BL , Klein-Szanto A , Pugacheva EN , Hardy RR , Wolfson M , Connolly DC , Golemis EA
NEDD9 Promotes Oncogenic Signaling in Mammary Tumor Development
Cancer Research. 2009 Sep;69(18) :7198-7206
PMID: 19738060    PMCID: PMC2768619    URL: https://www.ncbi.nlm.nih.gov/pubmed/19738060
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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 ART, 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]
Izumchenko, Eugene Singh, Mahendra K. Plotnikova, Olga V. Tikhmyanova, Nadezhda Little, Joy L. Serebriiskii, Ilya G. Seo, Sachiko Kurokawa, Mineo Egleston, Brian L. Klein-Szanto, Andres Pugacheva, Elena N. Hardy, Richard R. Wolfson, Marina Connolly, Denise C. Golemis, Erica A. Amer assoc cancer research Philadelphia 496fc