NEDD9 promotes oncogenic signaling in mammary tumor development

Eugene Izumchenko, Mahendra K Singh, Olga 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 journalArticleResearchpeer-review

94 Citations (Scopus)

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
Pages (from-to)7198 - 7206
Number of pages9
JournalCancer Research
Volume69
Issue number18
DOIs
Publication statusPublished - 2009
Externally publishedYes

Cite this

Izumchenko, E., Singh, M. K., Plotnikova, O., 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