Background

Recent studies suggested that crosstalk between ERα and EGFR/HER2 pathways plays a critical role in mediating endocrine therapy resistance. Several inhibitors targeting EGFR/HER2 signaling, including FDA-approved lapatinib and gefitinib as well as a novel dual tyrosine kinase inhibitor (TKI) sapitinib, showed greater therapeutic efficacies. However, how 3D chromatin landscape responds to the inhibition of EGFR/HER2 pathway remains to be elucidated.

Methods

In this study, we conducted in situ Hi-C and RNA-seq in two ERα+ breast cancer cell systems, 1) parental MCF7 cells and its associated tamoxifen-resistant MCF7TR cells; and 2) parental T47D cells and its associated tamoxifen-resistant T47DTR cells, before and after the treatment of sapitinib.

Results

We identified differential responses in topologically associated domains (TADs), looping genes and expressed genes. Interestingly, we found that many differential TADs and looping genes are reversible after sapitinib treatment, indicating that EGFR/HER2 signaling may play a role in reshaping and rewiring the high order genome organization. We further examined and recapitulated the reversible looping genes in 3D spheroids of breast cancer cells, demonstrating that 3D cell culture spheroid of breast cancer cells could be a potential preclinical breast cancer model for studying 3D chromatin regulation.

Conclusions

Our study has provided significant insights into our understanding of 3D genomic landscape changes in response to EGFR/HER2 Inhibition in endocrine-resistant breast cancer cells. Our data provides a rich resource for further evaluating chromatin structural responses to EGFR/HER2 targeted therapies in endocrine-resistant breast cancer cells. Our analyses suggest that these alterations of chromatin structures and transcriptional programs may provide new avenues for intervention or designing of patient selection for targeted endocrine treatment.

中文翻译：

---

内分泌抗性乳腺癌细胞对EGFR / HER2抑制差异反应的3D基因组格局。

背景

最近的研究表明，ERα和EGFR / HER2通路之间的串扰在介导内分泌治疗耐药性中起关键作用。几种针对EGFR / HER2信号转导的抑制剂，包括FDA批准的拉帕替尼和吉非替尼，以及新型双重酪氨酸激酶抑制剂（TKI）沙必替尼，显示出更高的治疗效果。然而，尚需阐明3D染色质格局如何响应EGFR / HER2途径的抑制。

方法

在这项研究中，我们在两个ERα+乳腺癌细胞系统中进行了原位Hi-C和RNA-seq的研究：1）亲本MCF7细胞及其相关的他莫昔芬耐药MCF7TR细胞；2）赛匹替尼治疗前后的亲本T47D细胞及其相关的他莫昔芬耐药性T47DTR细胞。

结果

我们确定了拓扑相关域（TADs），循环基因和表达的基因中的差异反应。有趣的是，我们发现在沙必替尼治疗后，许多差异性TAD和环状基因是可逆的，这表明EGFR / HER2信号传导可能在重塑和重新排列高阶基因组组织中起作用。我们进一步检查并概括了乳腺癌细胞3D球体中的可逆循环基因，表明乳腺癌细胞的3D细胞培养球体可能是研究3D染色质调控的潜在临床前乳腺癌模型。

结论

我们的研究为我们对内分泌抗性乳腺癌细胞响应EGFR / HER2抑制对3D基因组格局变化的理解提供了重要的见识。我们的数据为进一步评估内分泌抗性乳腺癌细胞对EGFR / HER2靶向疗法的染色质结构反应提供了丰富的资源。我们的分析表明，染色质结构和转录程序的这些改变可能为干预或设计针对内分泌治疗的患者选择提供新的途径。