Hi-C profiling in tissues reveals 3D chromatin-regulated breast tumor heterogeneity informing a looping-mediated therapeutic avenue.

The limitations of Hi-C (high-throughput chromosome conformation capture) profiling in in vitro cell culture include failing to recapitulate disease-specific physiological properties and lacking a clinically relevant disease microenvironment. In this study, we conduct Hi-C profiling in a pilot cohort of 12 breast tissues comprising two normal tissues, five ER+ breast primary tumors, and five tamoxifen-treated recurrent tumors. We demonstrate 3D chromatin-regulated breast tumor heterogeneity and identify a looping-mediated target gene, CA2, which might play a role in driving tamoxifen resistance. The inhibition of CA2 impedes tumor growth both in vitro and in vivo and reverses chromatin looping. The disruption of CA2 looping reduces tamoxifen-resistant cancer cell proliferation, decreases CA2 mRNA and protein expression, and weakens the looping interaction. Our study thus provides mechanistic and functional insights into the role of 3D chromatin architecture in regulating breast tumor heterogeneity and informs a new looping-mediated therapeutic avenue for treating breast cancer.