Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer

Joanna Achinger-Kawecka, Fatima Valdes-Mora, Phuc-Loi Luu, Katherine A. Giles, C. Elizabeth Caldon, Wenjia Qu, Shalima Nair, Sebastian Soto, Warwick J. Locke, Nicole S. Yeo-Teh, Cathryn M. Gould, Qian Du, Grady C. Smith, Irene R. Ramos, Kristine F. Fernandez, Dave S. Hoon, Julia M. W. Gee, Clare Stirzaker and Susan J. Clark ()
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Joanna Achinger-Kawecka: Garvan Institute of Medical Research
Fatima Valdes-Mora: Garvan Institute of Medical Research
Phuc-Loi Luu: Garvan Institute of Medical Research
Katherine A. Giles: Garvan Institute of Medical Research
C. Elizabeth Caldon: The Kinghorn Cancer Centre
Wenjia Qu: Garvan Institute of Medical Research
Shalima Nair: Garvan Institute of Medical Research
Sebastian Soto: Garvan Institute of Medical Research
Warwick J. Locke: Garvan Institute of Medical Research
Nicole S. Yeo-Teh: Garvan Institute of Medical Research
Cathryn M. Gould: Garvan Institute of Medical Research
Qian Du: Garvan Institute of Medical Research
Grady C. Smith: Garvan Institute of Medical Research
Irene R. Ramos: John Wayne Cancer Institute
Kristine F. Fernandez: The Kinghorn Cancer Centre
Dave S. Hoon: John Wayne Cancer Institute
Julia M. W. Gee: Cardiff University
Clare Stirzaker: Garvan Institute of Medical Research
Susan J. Clark: Garvan Institute of Medical Research

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. We observe that loss of 3D chromatin interactions often occurs coincidently with hypermethylation and loss of ER binding. Alterations in active A and inactive B chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.

Date: 2020
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DOI: 10.1038/s41467-019-14098-x

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