Neural precursor cell-Expressed Developmentally Down regulated gene 9 (NEDD9;HEF1, CAS-L) is a scaffolding protein regulating mitosis, survival, and migration. Within the last 3 years, NEDD9 has been implicated in the progression and metastasis of several cancers. Recently, a viable and fertile Nedd9 knockout strain has been developed that enables evaluation of the in vivo role of NEDD9 in cancer initiation and progression. Nedd9-/- mice were crossed to MMTV-neu (HER2;ErbB2) transgenic mice, and compared with MMTV-neu;Nedd9+/+ counterparts. Strikingly, by 18 months, 88% of MMTV-neu;Nedd9+/+ mice developed tumors, in contrast to only 18% of MMTV-neu;Nedd9-/- mice. This indicates a novel role for NEDD9 in the initiation of mammary tumor genesis, in contrast to progression. The project goal is to understand why the Nedd9-/- genotype reduces tumor incidence. MMTV-neu tumors commonly develop missense mutations in p53 to enhance tumor formation and progression after a significant period of latency (7-12 months), paralleling the observed functional loss of p53 in human HER2-overexpressing tumors. Aurora A kinase (AURKA) has recently emerged as a negative regulator of p53 activity and stability. Work from our laboratory has recently shown NEDD9 synergizes with a second protein, Ajuba, to positively and directly regulate AURKA. We have shown that siRNA-mediated knockdown of NEDD9 not only inhibits AURKA activity, but lowers AURKA protein levels. These results imply that in MMTV-neu;Nedd9-/- mammary epithelial cells, there would be low levels of AURKA protein, with commensurate failure to inhibit p53. In turn, early MMTV- neu;Nedd9-/- mammary epithelium would retain p53-dependent tumor suppression longer than the MMTV-neu;Nedd9+/+ epithelial cells, causing resistance to tumor formation. This proposal aims to investigate the NEDD9-AURKA interaction in MMTV-neu-driven mammary tumorigenesis. We will use techniques to investigate the status and functional implications of AURKA-p53 feedback in reference to the links already established between NEDD9, AURKA, and Ajuba. In addition, we will determine whether Nedd9 status affects therapeutic sensitivity of MMTV-neu tumors to AURKA inhibitors.
Changes in NEDD9 protein expression drive metastasis in more than 30% of human melanomas, and also have been linked to metastatic behavior in glioblastomas, lung cancers, and breast cancers. The proposed work builds from our prior studies analyzing NEDD9 interaction with the proto-oncogenic AURKA and investigates a novel role for NEDD9 in mammary tumor initiation that may reveal points of breast cancer cell vulnerability that can be therapeutically exploited.
|Little, J L; Serzhanova, V; Izumchenko, E et al. (2014) A requirement for Nedd9 in luminal progenitor cells prior to mammary tumorigenesis in MMTV-HER2/ErbB2 mice. Oncogene 33:411-20|