title: Network modeling links breast cancer susceptibility and centrosome dysfunction.
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.
authors.affiliation: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, 44 Binney St., Boston, Massachusetts 02115, USA.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Pujana
authors.forename: Jing-Dong J
authors.initials: JD
authors.lastname: Han
authors.forename: Lea M
authors.initials: LM
authors.lastname: Starita
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Stevens
authors.forename: Muneesh
authors.initials: M
authors.lastname: Tewari
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Ahn
authors.forename: Gad
authors.initials: G
authors.lastname: Rennert
authors.forename: Víctor
authors.initials: V
authors.lastname: Moreno
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhoff
authors.forename: Bert
authors.initials: B
authors.lastname: Gold
authors.forename: Volker
authors.initials: V
authors.lastname: Assmann
authors.forename: Wael M
authors.initials: WM
authors.lastname: Elshamy
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Rual
authors.forename: Douglas
authors.initials: D
authors.lastname: Levine
authors.forename: Laura S
authors.initials: LS
authors.lastname: Rozek
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Gelman
authors.forename: Kristin C
authors.initials: KC
authors.lastname: Gunsalus
authors.forename: Roger A
authors.initials: RA
authors.lastname: Greenberg
authors.forename: Bijan
authors.initials: B
authors.lastname: Sobhian
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bertin
authors.forename: Kavitha
authors.initials: K
authors.lastname: Venkatesan
authors.forename: Nono
authors.initials: N
authors.lastname: Ayivi-Guedehoussou
authors.forename: Xavier
authors.initials: X
authors.lastname: Solé
authors.forename: Pilar
authors.initials: P
authors.lastname: Hernández
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Weber
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cusick
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Parvin
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
mesh_terms: D064127:Aurora Kinases; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D018385:Centrosome / Q000502:physiology*; D019295:Computational Biology; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D016571:Neural Networks, Computer; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D025801:Ubiquitin; C098946:hyaluronan-mediated motility receptor; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases