Necdin is a breast cancer metastasis suppressor that regulates the transcription of c-Myc
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Minnkyong Lee1, Sarah M. Beggs1, Derek Gildea2, Sujata Bupp1, Jens Lichtenberg1, Niraj S. Trivedi2, NISC Comparative Sequencing Program3, Ying Hu4, David M. Bodine1 and Nigel P.S. Crawford1
1 Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA
2 Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA
3 NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Bethesda MD, USA
4 Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville MD, USA
Nigel P.S. Crawford, email:
Keywords: Necdin, c-Myc, germline polymorphisms, metastasis suppressors, breast cancer
Received: July 13, 2015 Accepted: August 12, 2015 Published: August 19, 2015
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.
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