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Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain

dc.contributor.authorCai, Wesley L.
dc.contributor.authorGreer, Celeste B.
dc.contributor.authorChen, Jocelyn F.
dc.contributor.authorArnal-Estape, Anna
dc.contributor.authorCao, Jian
dc.contributor.authorYan, Qin
dc.contributor.authorNguyen, Don X.
dc.identifier.citationCai, W. L., Greer, C. B., Chen, J. F., Arnal-Estapé, A., Cao, J., Yan, Q., & Nguyen, D. X. (2020). Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain. BMC medical genomics, 13(1), 33.
dc.identifier.othereISSN: 1755-8794
dc.description.abstractBackground Few somatic mutations have been linked to breast cancer metastasis, whereas transcriptomic differences among primary tumors correlate with incidence of metastasis, especially to the lungs and brain. However, the epigenomic alterations and transcription factors (TFs) which underlie these alterations remain unclear. Methods To identify these, we performed RNA-seq, Chromatin Immunoprecipitation and sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) of the MDA-MB-231 cell line and its brain (BrM2) and lung (LM2) metastatic sub-populations. We incorporated ATAC-seq data from TCGA to assess metastatic open chromatin signatures, and gene expression data from human metastatic datasets to nominate transcription factor biomarkers. Results Our integrated epigenomic analyses found that lung and brain metastatic cells exhibit both shared and distinctive signatures of active chromatin. Notably, metastatic sub-populations exhibit increased activation of both promoters and enhancers. We also integrated these data with chromosome conformation capture coupled with ChIP-seq (HiChIP) derived enhancer-promoter interactions to predict enhancer-controlled pathway alterations. We found that enhancer changes are associated with endothelial cell migration in LM2, and negative regulation of epithelial cell proliferation in BrM2. Promoter changes are associated with vasculature development in LM2 and homophilic cell adhesion in BrM2. Using ATAC-seq, we identified a metastasis open-chromatin signature that is elevated in basal-like and HER2-enriched breast cancer subtypes and associates with worse prognosis in human samples. We further uncovered TFs associated with the open chromatin landscapes of metastatic cells and whose expression correlates with risk for metastasis. While some of these TFs are associated with primary breast tumor subtypes, others more specifically correlate with lung or brain metastasis. Conclusions We identify distinctive epigenomic properties of breast cancer cells that metastasize to the lung and brain. We also demonstrate that signatures of active chromatin sites are partially linked to human breast cancer subtypes with poor prognosis, and that specific TFs can independently distinguish lung and brain relapse.en_US
dc.description.sponsorshipThis work was supported by the Department of Defense Breast Cancer Research Program Awards W81XWH-15-1-0117 (to QY); National Institutes of Health R01CA166376 and R01CA191489 (to DXN), F31CA243295 (to JFC), and P30 CA16359 (to Yale Comprehensive Cancer Center); National Science Foundation Graduate Research Fellowship DGE-1122492 (to WLC). The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.en_US
dc.publisherBMC Medica Genomicsen_US
dc.rightsOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
dc.subjectBreast canceren_US
dc.subjectTranscription factorsen_US
dc.subjectmRNA expressionen_US
dc.titleSpecific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brainen_US

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