Choppavarapu Lavanya, Fang Kun, Liu Tianxiang, Ohihoin Aigbe G, Jin Victor X
Divison of Biostatistics, Data Science Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Cell and Developmental Biology PhD program, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Cell Rep. 2025 Apr 22;44(4):115450. doi: 10.1016/j.celrep.2025.115450. Epub 2025 Mar 18.
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.
高通量染色体构象捕获（Hi-C）分析在体外细胞培养中的局限性包括无法重现疾病特异性生理特性以及缺乏临床相关的疾病微环境。在本研究中，我们对一个包含12个乳腺组织的试点队列进行了Hi-C分析，其中包括两个正常组织、五个雌激素受体阳性（ER+）乳腺原发性肿瘤和五个他莫昔芬治疗后的复发性肿瘤。我们证明了三维染色质调节的乳腺肿瘤异质性，并鉴定出一个环状介导的靶基因CA2，它可能在驱动他莫昔芬耐药中发挥作用。抑制CA2可在体外和体内阻碍肿瘤生长，并逆转染色质环化。CA2环化的破坏减少了他莫昔芬耐药癌细胞的增殖，降低了CA2 mRNA和蛋白表达，并减弱了环状相互作用。因此，我们的研究为三维染色质结构在调节乳腺肿瘤异质性中的作用提供了机制和功能方面的见解，并为治疗乳腺癌提供了一条新的环状介导的治疗途径。
