NEDD9 promotes oncogenic signaling in mammary tumor development

Eugene Izumchenko, Mahendra K. Singh, Olga V. Plotnikova, Nadezhda Tikhmyanova, Joy L. Little, Ilya G. Serebriiskii, Sachiko Seo, Mineo Kurokawa, Brian L. Egleston, Andres Klein-Szanto, Elena N. Pugacheva, Richard R. Hardy, Marina Wolfson, Denise C. Connolly, Erica A. Golemis

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7198-7206
Number of pages9
JournalCancer Research
Volume69
Issue number18
DOIs
StatePublished - Oct 13 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Izumchenko, E., Singh, M. K., Plotnikova, O. V., Tikhmyanova, N., Little, J. L., Serebriiskii, I. G., Seo, S., Kurokawa, M., Egleston, B. L., Klein-Szanto, A., Pugacheva, E. N., Hardy, R. R., Wolfson, M., Connolly, D. C., & Golemis, E. A. (2009). NEDD9 promotes oncogenic signaling in mammary tumor development. Cancer Research, 69(18), 7198-7206. https://doi.org/10.1158/0008-5472.CAN-09-0795