title: NEDD9 promotes oncogenic signaling in mammary tumor development.
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.
authors.affiliation: Program in Molecular and Translational Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Izumchenko
authors.forename: Mahendra K
authors.initials: MK
authors.lastname: Singh
authors.forename: Olga V
authors.initials: OV
authors.lastname: Plotnikova
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Tikhmyanova
authors.forename: Joy L
authors.initials: JL
authors.lastname: Little
authors.forename: Ilya G
authors.initials: IG
authors.lastname: Serebriiskii
authors.forename: Sachiko
authors.initials: S
authors.lastname: Seo
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Brian L
authors.initials: BL
authors.lastname: Egleston
authors.forename: Andres
authors.initials: A
authors.lastname: Klein-Szanto
authors.forename: Elena N
authors.initials: EN
authors.lastname: Pugacheva
authors.forename: Richard R
authors.initials: RR
authors.lastname: Hardy
authors.forename: Marina
authors.initials: M
authors.lastname: Wolfson
authors.forename: Denise C
authors.initials: DC
authors.lastname: Connolly
authors.forename: Erica A
authors.initials: EA
authors.lastname: Golemis
mesh_terms: 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
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505592:NEDD9 protein, mouse; D011506:Proteins; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse