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: Minnkyong Lee, Sarah M Beggs, Derek Gildea, Sujata Bupp, Jens Lichtenberg, Niraj S Trivedi, NISC Comparative Sequencing Program, Ying Hu, David M Bodine, Nigel P S Crawford
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 31 Pg. 31557-68 (Oct 13 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26384308 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• MYC protein, human
• Nerve Tissue Proteins
• Nuclear Proteins
• Proto-Oncogene Proteins c-myc
• RNA, Messenger
• necdin

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Proliferation
• Chromatin Immunoprecipitation
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Germ-Line Mutation (genetics)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Staging
• Nerve Tissue Proteins (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Prognosis
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays