Journal
CANCER RESEARCH
Volume 69, Issue 18, Pages 7198-7206Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-09-0795
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Funding
- NIH [RO1 CA63366, CA113342, CA-06927]
- Anny Materiel Command [W81XWH-07-1-0676]
- Pennsylvania Tobacco Settlement
- Israel Cancer Association and Stanley Abersur Research Foundation
- Pew Charitable Fund
- Ben-Gurion University of the Negev [T32 CA-009035]
- National Cancer Institute [PA50 CA-083638]
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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 ART, 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. [Cancer Res 2009;69(18):7198-206]
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