Estrogen receptor 1 chromatin profiling in human breast tumors reveals high inter-patient heterogeneity with enrichment of risk SNPs and enhancer activity at most-conserved regions
- Stacey E.P. Joosten1,2,14,
- Sebastian Gregoricchio1,2,14,
- Suzan Stelloo2,3,
- Elif Yapıcı4,5,
- Chia-Chi Flora Huang6,
- Kerim Yavuz6,
- Maria Donaldson Collier1,2,
- Tunç Morova6,
- Umut Berkay Altintaş6,
- Yongsoo Kim7,
- Sander Canisius8,9,
- Cathy B. Moelans10,
- Paul J. van Diest10,
- Gozde Korkmaz4,5,
- Nathan A. Lack4,5,6,
- Michiel Vermeulen2,3,11,
- Sabine C. Linn8,10,12 and
- Wilbert Zwart1,2,13
- 1Division of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
- 2Oncode Institute, The Netherlands;
- 3Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6500HB Nijmegen, The Netherlands;
- 4Koç University School of Medicine, 34450 Istanbul, Turkey;
- 5Koç University Research Center for Translational Medicine (KUTTAM), 34450 Istanbul, Turkey;
- 6Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, V6H 3Z6 Canada;
- 7Department of Pathology, Amsterdam University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands;
- 8Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
- 9Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
- 10Department of Pathology, Utrecht University Medical Centre, 3584 CX Utrecht, The Netherlands;
- 11Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
- 12Department of Medical Oncology, Antoni van Leeuwenhoek Hospital, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
- 13Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands
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↵14 These authors contributed equally to this work.
Abstract
Estrogen Receptor 1 (ESR1; also known as ERα, encoded by ESR1 gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications. Here, we use a large set of ESR1 ChIP-seq data from 70 ESR1+ breast cancers to explore inter-patient heterogeneity in ESR1 DNA binding to reveal a striking inter-tumor heterogeneity of ESR1 action. Of note, commonly shared ESR1 sites show the highest estrogen-driven enhancer activity and are most engaged in long-range chromatin interactions. In addition, the most commonly shared ESR1-occupied enhancers are enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ESR1 and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we can confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ESR1–chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ESR1 landscape, with the most common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.278680.123.
- Received October 30, 2023.
- Accepted April 11, 2024.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see https://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.