Repository logo
 

Regulators of genetic risk of breast cancer identified by integrative network analysis.


Type

Article

Change log

Authors

Castro, Mauro AA 
de Santiago, Ines 
Campbell, Thomas M 
Vaughn, Courtney 

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.

Description

Keywords

Breast Neoplasms, Cell Line, Tumor, Chromatin Immunoprecipitation, Cluster Analysis, Estrogen Receptor alpha, Female, Fibroblast Growth Factor 10, Gene Expression Profiling, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mutation, Quantitative Trait Loci, Reproducibility of Results, Transcription Factors

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

48

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (C14303/A17197)
Cancer Research UK (CB4320)
Cancer Research UK (A19274)
This work was funded by Cancer Research UK and the Breast Cancer Research Foundation. MAAC is funded by the National Research Council (CNPq) of Brazil. TEH held a fellowship from the US DOD Breast Cancer Research Program (W81XWH-11-1-0592) and is currently supported by an RAH Career Development Fellowship (Australia). TEH and WDT are funded by the NHMRC of Australia (NHMRC) (ID: 1008349 WDT; 1084416 WDT, TEH) and Cancer Australia/National Breast Cancer Foundation (ID 627229; WDT, TEH). BAJP is a Gibb Fellow of Cancer Research UK. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited.