Enhanced genetic instability and dasatinib sensitivity in mammary tumor cells lacking NEDD9

Mahendra K. Singh, Eugene Izumchenko, Andres J. Klein-Szanto, Brian L. Egleston, Marina Wolfson, Erica A. Golemis

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Elevated expression of the NEDD9/HEF1/Cas-L scaffolding protein promotes tumor cell invasion and metastasis in multiple cancer cell types. Conversely, generation of mammary tumors in the mouse mammary tumor virus (MMTV)-polyoma virus middle T (PyVT) genetic model is delayed by a Nedd9-/- genotype. These activities arise from the role of NEDD9 in assembling complexes and supporting activity of cancer signaling proteins, including FAK, Src, Shc, and AKT, and would support evaluation of NEDD9 expression as an unambiguous biomarker for tumor aggressiveness. However, we here show that despite the initial delay in tumor growth, cells derived from MMTV-PyVT;Nedd9-/- tumors are characteristically hyperaggressive versus MMTV-PyVT;Nedd9 +/+ cells in anchorage-independent growth, in growth on three-dimensional matrix produced by tumor-associated fibroblasts, and in formation of tumors after mammary orthotopic reinjection and of lung metastases after tail vein injection. This reversal suggests the specific selection of MMTV-PyVT;Nedd9-/- cells for growth in an in vivo microenvironment. Indeed, MMTV-PyVT;Nedd9-/- cells have increased cell cycle, centrosomal, and mitotic defects, phenotypes compatible with the increased selection of these cells for aggressive growth. Intriguingly, in spite of their aggressive phenotype, MMTV-PyVT;Nedd9-/- cells persistently have low levels of Src activation and are hypersensitive to the Src kinase inhibitor dasatinib. These studies identify NEDD9 as a complex modulator of different aspects of mammary tumor growth.

Original languageEnglish (US)
Pages (from-to)8907-8916
Number of pages10
JournalCancer Research
Volume70
Issue number21
DOIs
StatePublished - Nov 1 2010

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Singh, M. K., Izumchenko, E., Klein-Szanto, A. J., Egleston, B. L., Wolfson, M., & Golemis, E. A. (2010). Enhanced genetic instability and dasatinib sensitivity in mammary tumor cells lacking NEDD9. Cancer Research, 70(21), 8907-8916. https://doi.org/10.1158/0008-5472.CAN-10-0353