NEDD9 promotes oncogenic signaling in mammary tumor development.
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.
Izumchenko
Eugene
E
Program in Molecular and Translational Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Singh
Mahendra K
MK
Plotnikova
Olga V
OV
Tikhmyanova
Nadezhda
N
Little
Joy L
JL
Serebriiskii
Ilya G
IG
Seo
Sachiko
S
Kurokawa
Mineo
M
Egleston
Brian L
BL
Klein-Szanto
Andres
A
Pugacheva
Elena N
EN
Hardy
Richard R
RR
Wolfson
Marina
M
Connolly
Denise C
DC
Golemis
Erica A
EA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C505592:NEDD9 protein, mouse; D011506:Proteins; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse