@article{c1867589fbd349e09a41891db90444c4,
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.",
author = "Pujana, {Miguel Angel} and Han, {Jing Dong J} and Starita, {Lea M.} and Stevens, {Kristen N.} and Muneesh Tewari and Ahn, {Jin Sook} and Gad Rennert and V{\'i}ctor Moreno and Tomas Kirchhoff and Bert Gold and Volker Assmann and Elshamy, {Wael M.} and Rual, {Jean Fran{\c c}ois} and Douglas Levine and Rozek, {Laura S.} and Gelman, {Rebecca S.} and Gunsalus, {Kristin C.} and Greenberg, {Roger A.} and Bijan Sobhian and Nicolas Bertin and Kavitha Venkatesan and Nono Ayivi-Guedehoussou and Xavier Sol{\'e} and Pilar Hern{\'a}ndez and Conxi L{\'a}zaro and Nathanson, {Katherine L.} and Weber, {Barbara L.} and Cusick, {Michael E.} and Hill, {David E.} and Kenneth Offit and Livingston, {David M.} and Gruber, {Stephen B.} and Parvin, {Jeffrey D.} and Marc Vidal",
note = "Funding Information: We thank members of our laboratories for discussion and comments on the manuscript; A. Merdes (Wellcome Trust Centre for Cell Biology) for anti-PCM1; B. Koch (Research Institute of Molecular Pathology) for anti-CSPG6 and anti-SMC1L1; K.-T. Jeang (National Institute of Allergy and Infectious Disease) for anti-MAD1L1 (Dap23); D.-Y. Jin (University Hong Kong) for anti-MAD1L1 (81d); E.A. Nigg (Max Planck Institute of Biochemistry) for anti-CEP2; D.R. Scoles (University California Los Angeles) for providing constructs; V. Joulov for sharing results before publication; C. McCowan, T. Clingingsmith and C. You for administrative assistance; and K. Salehi-Ashtiani, D. Szeto, R. Murray and C. Lin for characterizing the genomic structure of HMMR. L.M.S. was supported by a Department of Defense Breast Cancer Research Program fellowship and a grant from the National Cancer Institute (CA90281to J.D.P.). M.T. was supported by an award from the National Institutes of Health (NIH; K08-AG21613). K.C.G. received support from the US Army Medical Research Acquisition Activity (W23RYX-3275-N605) and NYSTAR (C040066). This work was supported by an NIH/National Cancer Institute (NCI) R33 grant (to M.V.), an NIH/NCI U01 grant (to S. Korsmeyer, S. Orkin, G. Gilliland and M.V.), an NIH/NCI ICBP grant (to J. Nevins and M.V.), an {\textquoteleft}interactome mapping{\textquoteright} grant from the NIH/ National Human Genome Research Institute and the NIH/National Institute of General Medical Sciences (to F. Roth and M.V.), an NIH/NCI P30 grant (CA046592 to the University of Michigan), a Spanish Ministry of Education and Science grant (PR2006-0474 to V.M.) and awards from the Breast Cancer Research Foundation (BCRF13740) and the Niehaus, Southworth, Weissenbach Foundation (to K.O.) and the Koodish Foundation (to T.K.). We also acknowledge the role of the New York Cancer Project, supported by the Academic Medicine Development Company of New York.",
year = "2007",
month = nov,
doi = "10.1038/ng.2007.2",
language = "English (US)",
volume = "39",
pages = "1338--1349",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "11",
}