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Singh MK , Izumchenko E , Klein-Szanto AJ , Egleston BL , Wolfson M , Golemis EA
Enhanced Genetic Instability and Dasatinib Sensitivity in Mammary Tumor Cells Lacking NEDD9
Cancer Research. 2010 Nov;70(21) :8907-8916
PMID: ISI:000283667300067    PMCID: PMC2970659   
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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. Cancer Res; 70(21); 8907-16. (C) 2010 AACR.
Notes
Singh, Mahendra K. Izumchenko, Eugene Klein-Szanto, Andres J. Egleston, Brian L. Wolfson, Marina Golemis, Erica A. NIH [R01-CA63366, R01-CA113342, CA-06927]; Army Materiel Command [W81XWH-07-1-0676]; Pennsylvania Tobacco Settlement funding ; Israel Cancer Association and Stanley Abersur Research Foundation ; Pew Charitable Trust (Fox Chase Cancer Center) ; American Associates, Ben-Gurion University of the Negev NIH grants R01-CA63366 and R01-CA113342; Army Materiel Command grant W81XWH-07-1-0676; the Pennsylvania Tobacco Settlement funding (E. A. Golemis); the Israel Cancer Association and Stanley Abersur Research Foundation (M. Wolfson); NIH core grant CA-06927 and the Pew Charitable Trust (Fox Chase Cancer Center); and the American Associates, Ben-Gurion University of the Negev (E. Izumchenko). 30 Amer assoc cancer research; 615 chestnut st, 17th floor, philadelphia, pa 19106-4404 usa 673mj