Abstract 3257: NEDD9 is required for initiation of HER2/Neu-dependent mammary tumor development

Abstract

Abstract Neural precursor cell-Expressed Developmentally Downregulated gene 9 (NEDD9; HEF1, CAS-L) is a scaffolding protein regulating mitosis, survival, and migration. Within the last 3 years, overexpression of NEDD9 has been implicated in the progression and metastasis of several cancers. Using a Nedd9 knockout strain, we have evaluated the in vivo requirement for NEDD9 in mammary tumorigenesis. Loss of Nedd9 increased the latency of tumor formation in the aggressive MMTV-Polyoma Virus middle T antigen (PyV(m)T) model of mammary tumorigenesis (Izumchenko et al. Cancer Res, 2009). We and others have shown that NEDD9 interacts with and positively regulates activity of key oncogenic signaling proteins such as Aurora-A kinase (AURKA) and Src in cell culture. Tumors harvested from MMTV-PyV(m)T;Nedd9−/− mice had greatly reduced activation of AURKA, SRC, and also FAK and AKT, with the lowest levels of activation correlating with the greatest delays in tumor onset. To explore the role of NEDD9 in a second highly physiological model of mammary tumorigenesis, Nedd9−/− mice were crossed to MMTV-neu (HER2; ErbB2) transgenic mice, and compared with MMTV-neu;Nedd9+/+ counterparts. Strikingly, after over 18 months, 89% of MMTV-neu;Nedd9+/+ mice developed tumors, in contrast to only 29% of MMTV-neu;Nedd9−/− mice. Between genotypes, there is no statistical difference between tumor growth rates or metastasis. Cell lines derived from tumors of both MMTV-neu;Nedd9+/+ and MMTV-neu;Nedd9−/− animals were then used for xenograft tumor growth and experimental metastasis assays. MMTV-neu;Nedd9−/− tumor-derived cell lines grew similarly to MMTV-neu;Nedd9+/+ counterparts as xenografts in the mammary fat pads of SCID mice, but metastasized to the lungs of SCID mice less readily following tail vein injection. These and other data indicate a novel role for NEDD9 in mammary tumor initiation distinct from the role controlling metastasis and progression of tumors in cooperation with the oncogenes FAK and SRC. Further, the work suggests that HER2-driven mammary tumorigenesis is dependent on NEDD9 at initial stages, but NEDD9 is not required for tumor maintenance, progression, or metastasis from primary organ sites. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3257.