title: A requirement for Nedd9 in luminal progenitor cells prior to mammary tumorigenesis in MMTV-HER2/ErbB2 mice.
abstract: Overexpression of the NEDD9/HEF1/Cas-L scaffolding protein is frequent, and drives invasion and metastasis in breast, head and neck, colorectal, melanoma, lung and other types of cancer. We have examined the consequences of genetic ablation of Nedd9 in the MMTV-HER2/ERBB2/neu mouse mammary tumor model. Unexpectedly, we found that only a limited effect on metastasis in MMTV-neu;Nedd9(-/-) mice compared with MMTV-neu;Nedd9(+/+) mice, but instead a dramatic reduction in tumor incidence (18 versus 80%), and a significantly increased latency until tumor appearance. Orthotopic reinjection and tail-vein injection of cells arising from tumors, coupled with in vivo analysis, indicated tumors arising in MMTV-neu;Nedd9(-/-) mice had undergone mutational selection that overcame the initial requirement for Nedd9. To better understand the defects in early tumor growth, we compared mammary progenitor cell pools from MMTV-neu;Nedd9(-/-) versus MMTV-neu;Nedd9(+/+) mice. The MMTV-neu;Nedd9(-/-) genotype selectively reduced both the number and colony-forming potential of mammary luminal epithelial progenitor cells, while not affecting basal epithelial progenitors. MMTV-neu;Nedd9(-/-) mammospheres had striking defects in morphology and cell polarity. All of these defects were seen predominantly in the context of the HER2/neu oncogene, and were not associated with randomization of the plane of mitotic division, but rather with depressed expression the cell attachment protein FAK, accompanied by increased sensitivity to small molecule inhibitors of FAK and SRC. Surprisingly, in spite of these significant differences, only minimal changes were observed in the gene expression profile of Nedd9(-/-) mice, indicating critical Nedd9-dependent differences in cell growth properties were mediated via post-transcriptional regulation of cell signaling. Coupled with emerging data indicating a role for NEDD9 in progenitor cell populations during the morphogenesis of other tissues, these results indicate a functional requirement for NEDD9 in the growth of mammary cancer progenitor cells.
authors: 1] Fox Chase Cancer Center, Institute of Cancer Research, Philadelphia, PA, USA [2] Department of Biology, Bryn Mawr College, Bryn Mawr, PA, USA.
authors: J L
authors: JL
authors: Little
authors: Fox Chase Cancer Center, Institute of Cancer Research, Philadelphia, PA, USA.
authors: V
authors: V
authors: Serzhanova
authors: Fox Chase Cancer Center, Institute of Cancer Research, Philadelphia, PA, USA.
authors: E
authors: E
authors: Izumchenko
authors: Fox Chase Cancer Center, Institute of Cancer Research, Philadelphia, PA, USA.
authors: B L
authors: BL
authors: Egleston
authors: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
authors: E
authors: E
authors: Parise
authors: Fox Chase Cancer Center, Institute of Cancer Research, Philadelphia, PA, USA.
authors: A J
authors: AJ
authors: Klein-Szanto
authors: Department of Biology, Bryn Mawr College, Bryn Mawr, PA, USA.
authors: G
authors: G
authors: Loudon
authors: Fox Chase Cancer Center, Institute of Cancer Research, Philadelphia, PA, USA.
authors: M
authors: M
authors: Shubina
authors: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: S
authors: S
authors: Seo
authors: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: M
authors: M
authors: Kurokawa
authors: Departments of Oncology and Health Science Informatics, Johns Hopkins University, Baltimore, MD, USA.
authors: M F
authors: MF
authors: Ochs
authors: Fox Chase Cancer Center, Institute of Cancer Research, Philadelphia, PA, USA.
authors: E A
authors: EA
authors: Golemis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505592:NEDD9 protein, mouse