Comparative characterization of 3D chromatin organization in triple-negative breast cancers

Abstract

Triple-negative breast cancer (TNBC) is a malignant cancer subtype with a high risk of recurrence and an aggressive phenotype compared to other breast cancer subtypes. Although many breast cancer studies conducted to date have investigated genetic variations and differential target gene expression, how 3D chromatin architectures are reorganized in TNBC has been poorly elucidated. Here, using in situ Hi-C technology, we characterized the 3D chromatin organization in cells representing five distinct subtypes of breast cancer (including TNBC) compared to that in normal cells. We found that the global and local 3D architectures were severely disrupted in breast cancer. TNBC cell lines (especially BT549 cells) showed the most dramatic changes relative to normal cells. Importantly, we detected CTCF-dependent TNBC-susceptible losses/gains of 3D chromatin organization and found that these changes were strongly associated with perturbed chromatin accessibility and transcriptional dysregulation. In TNBC tissue, 3D chromatin disorganization was also observed relative to the 3D chromatin organization in normal tissues. We observed that the perturbed local 3D architectures found in TNBC cells were partially conserved in TNBC tissues. Finally, we discovered distinct tissue-specific chromatin loops by comparing normal and TNBC tissues. In this study, we elucidated the characteristics of the 3D chromatin organization in breast cancer relative to normal cells/tissues at multiple scales and identified associations between disrupted structures and various epigenetic features and transcriptomes. Collectively, our findings reveal important 3D chromatin structural features for future diagnostic and therapeutic studies of TNBC. Cancer: Scrambled genomes found in aggressive breast tumors The 3D architecture of the genome is dramatically altered in an aggressive form of breast cancer, leading to changes in the regulation of gene expression that can fuel tumor growth. A team from South Korea, led by Hyeong-Gon Moon of Seoul National University College of Medicine and Daeyoup Lee of the Korea Advanced Institute of Science and Technology, Daejeon, detailed how chromosomes are positioned and folded within the nucleus of cell liness from five different subtypes of breast cancer. They found that triple-negative breast cancers displayed the most extreme reorganization of their genomes, a pattern also observed in biopsy tissues taken from patients with this subtype of cancer. Knowledge of these conformational changes could inform future efforts to develop therapies and diagnostics for patients with triple-negative breast tumors.