Subtype-specific circadian clock dysregulation modulates breast cancer biology, invasiveness, and prognosis.
Subtype-specific circadian clock dysregulation modulates breast cancer biology, invasiveness, and prognosis.
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亚型特异性生物钟失调调节乳腺癌生物学、侵袭性和预后。
DOI：
10.1101/2023.05.17.540386
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Anafi,RonC
中科院分区：
文献类型：
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作者：
Hammarlund,JanA;Li,Shi-Yang;Wu,Gang;Lian,Jia-Wen;Howell,SachaJ;Clarke,Rob;Adamson,Antony;Gonçalves,CátiaF;Hogenesch,JohnB;Meng,Qing-Jun;Anafi,RonC
对轮班工人和模式生物的研究表明，昼夜节律紊乱与乳腺癌有关。然而，非癌性和癌性人类乳腺组织中的分子节律在很大程度上是未知的。我们以非正式的方式重建节奏，将当地收集的、带有时间戳的活组织检查与公共数据集结合起来。对于非癌组织，核心昼夜节律基因的推断顺序与已建立的生理学相匹配。炎症、上皮-间质转化（EMT）和雌激素反应通路显示昼夜节律调节。在肿瘤中，时钟相关性分析显示了昼夜节律组织的亚型特异性变化。管腔A类器官和管腔A样本的信息有序表现出持续的，尽管节律中断。然而，在Luminal a样本中，CYCLOPS幅度(一种测量全球节奏强度的方法)差异很大。EMT通路基因的循环在高强度Luminal A肿瘤中明显增加。高大小肿瘤患者的5年生存率降低。相应地，3D Luminal A培养在分子钟中断后显示侵袭减少。这项研究将乳腺癌亚型特异性昼夜节律中断与EMT、转移潜力和预后联系起来。
Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular rhythms in non-cancerous and cancerous human breast tissues are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For non-cancerous tissue, the inferred order of core-circadian genes matches established physiology. Inflammatory, epithelial-mesenchymal transition (EMT), and estrogen responsiveness pathways show circadian modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes in circadian organization. Luminal A organoids and informatic ordering of Luminal A samples exhibit continued, albeit disrupted rhythms. However, CYCLOPS magnitude, a measure of global rhythm strength, varied widely among Luminal A samples. Cycling of EMT pathway genes was markedly increased in high-magnitude Luminal A tumors. Patients with high-magnitude tumors had reduced 5-year survival. Correspondingly, 3D Luminal A cultures show reduced invasion following molecular clock disruption. This study links subtype-specific circadian disruption in breast cancer to EMT, metastatic potential, and prognosis.