Abstract B106: Nedd9 null status initially delays mammary tumor growth, then selects for hyper-aggressive mammary tumors

Abstract

Abstract Altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has recently emerged as a candidate mechanism controlling tumor development, progression and metastasis. While some studies have identified elevated NEDD9 expression as pro-metastatic, other works have suggested a negative role in tumor progression. We have recently reported that the Nedd9 null genetic background significantly limits mammary tumor development in the MMTV-polyoma virus middle T (PyVmT) genetic model. Late-developing tumors are characterized by depressed activation of proteins including AKT, SRC, FAK, and ERK, emphasizing an important role of NEDD9 as a scaffolding protein for these pro-oncogenic proteins. However, NEDD9 is also regulates activation of the Aurora-A mitotic kinase (AurA). In vitro, knockdown of NEDD9 reduces AurA activation, suggesting in vivo loss of NEDD9 might be a potential source of genomic instability. We have evaluated a panel of cell lines derived from mammary tumors of MMTV-PyVmT;Nedd9−/− mice. Nedd9−/− cells injected orthotopically in mammary fat pads of SCID mice exhibited significantly faster growth of mammary tumors, and in a tail vein injection assay yielded a dramatically enhanced metastasis to the lungs. As hypothesized, Nedd9−/− cell lines had lower AurA kinase activity than Nedd9+/+ cells, and also had evidence of centrosomal and spindle abnormalities associated with deficient AurA function. Interestingly, the sensitivity of Nedd9−/− cells to small molecule inhibitors targeted at specific partner kinases and to chemotherapeutic agents used in breast cancer notably differed from that of Nedd9+/+ cells. Together, these data support the use of NEDD9 expression as a novel biomarker in establishing prognosis and drug responsiveness of tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B106.