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

• DOI: 10.1038/s41467-019-14098-x
• Publication Date: 2020-01-16T11:04:55Z
• Authors: Joanna Achinger-K...; 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. Ferna...; Dave S. Hoon; Julia M. W. Gee; Clare Stirzaker; Susan J. Clark
• Keywords: 0301 basic medicine; 570; CCCTC-Binding Factor; Antineoplastic Agents, Hormonal; Science; 610; 32 Biomedical and Clinical Sciences; Antineoplastic Agents; Breast Neoplasms; 3101 Biochemistry and Cell Biology; Article; Epigenesis, Genetic; Promoter Regions; 03 medical and health sciences; Cancer Genomics; anzsrc-for: 32 Biomedical and Clinical Sciences; Genetic; Breast Cancer; Receptors; Genetics; 2.1 Biological and endogenous factors; Humans; Protein Interaction Domains and Motifs; anzsrc-for: 31 Biological Sciences; Promoter Regions, Genetic; Cancer; anzsrc-for: 3211 Oncology and Carcinogenesis; Neoplastic; Binding Sites; Hormonal; Whole Genome Sequencing; Human Genome; anzsrc-for: 3101 Biochemistry and Cell Biology; Q; DNA Methylation; 3211 Oncology and Carcinogenesis; Estrogen; Chromatin; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; Gene Expression Regulation; Receptors, Estrogen; MCF-7 Cells; Women's Health; Female; 31 Biological Sciences; Epigenesis

AbstractEndocrine 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.