3D Epigenome Remodelling in Endocrine Resistant Breast Cancer

Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown (1). Here, we use high-resolution chromosome conformation capture (Hi-C) to show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine resistant breast cancer cells (2). We provide an important connection between genetic and epigenetics changes in endocrine resistant breast cancer by integrating chromatin contacts with whole-genome sequencing data, which highlights the role of resistance-associated genetic variants at CTCF-bound anchors in promoting differential interactions. Ectopic chromatin interactions are also 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. Importantly, loss of 3D chromatin interactions often occurs coincidently with DNA hyper-methylation and loss of ER binding. Alterations in active (A-type) and inactive (B-type) chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results demonstrate for the first time that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer providing new avenues for therapeutic targeting.

1. Stone, A. et al. DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer. Nature communications 6, 7758 (2015).

2. Achinger-Kawecka et al. Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer. Nature Commun 11, 320 (2020)