Network modeling links breast cancer susceptibility and centrosome dysfunction

Nat Genet. 2007 Nov;39(11):1338-49. doi: 10.1038/ng.2007.2. Epub 2007 Oct 7.

Abstract

Many cancer-associated genes remain to be identified to clarify the underlying molecular mechanisms of cancer susceptibility and progression. Better understanding is also required of how mutations in cancer genes affect their products in the context of complex cellular networks. Here we have used a network modeling strategy to identify genes potentially associated with higher risk of breast cancer. Starting with four known genes encoding tumor suppressors of breast cancer, we combined gene expression profiling with functional genomic and proteomic (or 'omic') data from various species to generate a network containing 118 genes linked by 866 potential functional associations. This network shows higher connectivity than expected by chance, suggesting that its components function in biologically related pathways. One of the components of the network is HMMR, encoding a centrosome subunit, for which we demonstrate previously unknown functional associations with the breast cancer-associated gene BRCA1. Two case-control studies of incident breast cancer indicate that the HMMR locus is associated with higher risk of breast cancer in humans. Our network modeling strategy should be useful for the discovery of additional cancer-associated genes.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aurora Kinases
  • BRCA1 Protein / antagonists & inhibitors
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • BRCA2 Protein / antagonists & inhibitors
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Centrosome / physiology*
  • Computational Biology
  • Extracellular Matrix Proteins / antagonists & inhibitors
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Female
  • Gene Expression Profiling
  • Gene Regulatory Networks*
  • Genetic Predisposition to Disease
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Neural Networks, Computer*
  • Oligonucleotide Array Sequence Analysis
  • Polymerase Chain Reaction
  • Protein Interaction Mapping
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / pharmacology
  • Ubiquitin / metabolism

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • Biomarkers, Tumor
  • Extracellular Matrix Proteins
  • Hyaluronan Receptors
  • RNA, Small Interfering
  • Ubiquitin
  • hyaluronan-mediated motility receptor
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases