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 À/À 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 À/À 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.

Nedd9 restrains renal cystogenesis in Pkd1 −/− mice

“…NEDD9 (also known as HEF1 and Cas-L) is a scaffold for cell signaling interactions that govern cell attachment and migration (4, 5), survival (6), mitogenic signaling and cell cycle control (7)(8)(9)(10), and ciliary resorption (11,12). To date, NEDD9 has been most studied in the context of cancer, because deregulated expression of NEDD9 accompanies and promotes metastasis in a large and growing number of cancer types, whereas genetic ablation of NEDD9 has a significant modifier function for tumor initiation and progression (8,13,14).…”

“…To date, NEDD9 has been most studied in the context of cancer, because deregulated expression of NEDD9 accompanies and promotes metastasis in a large and growing number of cancer types, whereas genetic ablation of NEDD9 has a significant modifier function for tumor initiation and progression (8,13,14). A particularly interesting feature of NEDD9 action in cancer is that both overexpression and loss of function have been found to be tumor promoting different cellular contexts, likely because either form of disruption of its scaffolding action impairs downstream processes.…”

Dendrosomal Curcumin Inhibits Metastatic Potential of Human SW480 Colon Cancer Cells through Down-regulation of Claudin1, Zeb1 and Hef1-1 Gene Expression

“…Hef1, also known as NEDD9, is a multi-domain scaffolding protein of the Cas family, that localizes to focal adhesions to coordinate FAK and Src signaling cascades in integrin-dependent adhesion and migration. High levels of Hef1 have been reported in various human cancers including melanoma, lung cancer and colon cancer (Kim et al, 2006;Ji et al, 2007;Izumchenko et al, 2009;Li et al, 2011). Tight junctions play a major role in establishment and maintenance of cell polarity, differentiation, and controlling cell motility and invasiveness.…”

“…Overexpression of Zeb1, Hef1 and claudin 1 has been implicated in promotion of cell migration and metastasis in various types of cancers. Vice versa, a knockdown of Zeb1, Hef1 and Claudin 1 factors with siRNA or shRNA in undifferentiated cancer cells such as SW480 cells resulted in metastasis inhibition (Sarah et al, 2002;Leu et al, 2003;Ray et al, 2003;Conroy et al, 2005;Natarajan et al, 2006;Sita et al, 2006;Spaderna et al, 2006;Su, 2006a;Aigner et al, 2007;Ji et al, 2007;Izumchenko et al, 2009;Wellner et al, 2009;Myal et al, 2010;Amar et al, 2011;Li et al, 2011;Chen et al, 2012;Sanchez-Tillo et al, 2013). To date, few studies have investigated the molecular mechanisms through which curcumin inhibits metastasis: Amitava Chatterjee et al suggested that curcumin impedes cell metastasis by inhibiting the expression of cell adhesions molecules such as integrin receptors, focal adhesion kinase (FAK) and enhances the expression of E-cadherin (Ray et al, 2003).…”

Expression of growth hormone receptor, plakoglobin and NEDD9 protein in association with tumour progression and metastasis in human breast cancer

“…In vitro studies showed that overproduction of HEF1 in MCF7 breast carcinoma cells promotes cell spreading and migration, and increases levels of mRNA transcripts encoding proteins that are associated with motility, cell transformation and invasiveness [33]. The first in vivo evidence linking NEDD9 with breast cancer aggressiveness came from the study demonstrating that genetic deletion of NEDD9 significantly limits early tumour development and diminishes cell spreading and migration in a mouse model of mammary tumour development [34]. Lack of NEDD9 caused marked down-regulation of pro-oncogenic signalling pathways including AKT, Src, FAK, and ERK in the late-appearing Nedd9(-/-) tumours, pointing to the role of Nedd9 as a scaffolding protein for these proteins.…”