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.
Highlights
Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown
To initially address if 3D epigenetic remodelling is associated with endocrine resistance, independent of the class of endocrine therapy, we performed in situ Hi-C experiments in parental endocrine-sensitive ER+ MCF7 cells, tamoxifen-resistant (TAMR)[15] cells and fulvestrant-resistant (FASR)[16] cells (Supplementary Table 1)
By integrating single-nucleotide variation (SNV) data obtained from whole genome sequencing (WGS) with differential interactions identified in TAMR and FASR cells, we investigated whether SNVs uniquely present in endocrine-resistant cells could directly alter individual differential 3D interactions
Summary
Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. We reported that differential DNA methylation at estrogen-responsive enhancers is associated with endocrine response in breast cancer[6], raising the possibility that dynamic three-dimensional (3D) chromatin remodelling of ER-mediated enhancer−promoter interactions could potentially underlie the development of endocrine resistance in breast cancer. These and related studies[6,8] did not directly interrogate the role of 3D genome architecture in association with such alterations. We show that 3D epigenome remodelling is a key mechanism associated with endocrine resistance that consists of aberrant DNA methylation and differential ER-bound enhancer −promoter interactions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
