title: Necdin is a breast cancer metastasis suppressor that regulates the transcription of c-Myc.
abstract: Metastasis is the primary cause of death in breast cancer. Earlier studies using a mammary tumorigenesis mouse model identified Necdin (Ndn)as a germline modifier of metastasis. Differential expression of Ndn induces a gene-expression signature that predicts prognosis in human breast cancer. Additionally, a non-synonymous germline single nucleotide polymorphism (T50C; V17A) in Ndn distinguishes mouse strains with differing metastatic capacities. To better understand how hereditary factors influence metastasis in breast cancer, we characterized NDN-mediated transcription. Haplotype analysis in a well-characterized breast cancer cohort revealed that NDN germline variation is associated with both NDN expression levels and patient outcome. To examine the role of NDN in mammary tumor metastasis and transcriptional regulation, mouse mammary tumor cell lines stably over-expressing either the wildtype 50T or variant 50C Ndn allele were generated. Cells over-expressing Ndn 50T, but not Ndn 50C, exhibited significant decrease in cell invasiveness and pulmonary metastases compared to control cells. Transcriptome analyses identified a 71-gene expression signature that distinguishes cells over-expressing the two Ndn allelic variants. Furthermore, ChIP assays revealed c-Myc, a target gene of NDN, to be differentially regulated by the allelic variants. These data demonstrate that NDN and the T50C allele regulate gene expression and metastasis efficiency.
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA.
authors.forename: Minnkyong
authors.initials: M
authors.lastname: Lee
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Beggs
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Gildea
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Bupp
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Lichtenberg
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA.
authors.forename: Niraj S
authors.initials: NS
authors.lastname: Trivedi
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville MD, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Bodine
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA.
authors.forename: Nigel P S
authors.initials: NP
authors.lastname: Crawford
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C489427:MYC protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C069766:necdin
keywords: breast cancer; c-Myc; germline polymorphisms; metastasis suppressors; necdin