title: Regulators of genetic risk of breast cancer identified by integrative network analysis.
abstract: Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.
authors.affiliation: Bioinformatics and Systems Biology Laboratory, Federal University of Paraná (UFPR), Polytechnic Center, Curitiba, Brazil.
authors.forename: Mauro A A
authors.initials: MA
authors.lastname: Castro
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.|Department of Oncology, University of Cambridge, Hutchison/Medical Research Council (MRC) Research Centre, Cambridge, UK.
authors.forename: Ines
authors.initials: I
authors.lastname: de Santiago
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.|Department of Oncology, University of Cambridge, Hutchison/Medical Research Council (MRC) Research Centre, Cambridge, UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Campbell
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.|Department of Oncology, University of Cambridge, Hutchison/Medical Research Council (MRC) Research Centre, Cambridge, UK.
authors.forename: Courtney
authors.initials: C
authors.lastname: Vaughn
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Theresa E
authors.identifier: http://orcid.org/0000-0002-2752-730X
authors.initials: TE
authors.lastname: Hickey
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Edith
authors.initials: E
authors.lastname: Ross
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Florian
authors.initials: F
authors.lastname: Markowetz
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.|Department of Oncology, University of Cambridge, Hutchison/Medical Research Council (MRC) Research Centre, Cambridge, UK.
authors.forename: Bruce A J
authors.initials: BA
authors.lastname: Ponder
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.|Department of Oncology, University of Cambridge, Hutchison/Medical Research Council (MRC) Research Centre, Cambridge, UK.
authors.forename: Kerstin B
authors.initials: KB
authors.lastname: Meyer
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation / Q000379:methods; D016000:Cluster Analysis; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009154:Mutation; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C496463:FGF10 protein, human; D051526:Fibroblast Growth Factor 10; D014157:Transcription Factors