Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom.
School of Biomedical Engineering, Science and Health Systems, Bossone Research Center, Drexel University, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2024 Feb 13;121(7):e2311854121. doi: 10.1073/pnas.2311854121. Epub 2024 Feb 6.
Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular circadian rhythms in noncancerous and cancerous human breast tissues and their clinical relevance are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For noncancerous breast tissue, 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 dampened and reprogrammed 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. Surprisingly, patients with high-magnitude tumors had reduced 5-y 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.
研究表明，轮班工人和模式生物的昼夜节律紊乱与乳腺癌有关。然而，非癌性和癌性人乳腺组织中的分子昼夜节律及其临床相关性在很大程度上尚不清楚。我们通过信息学方法重建了节律，将本地收集的、带有时间戳的活检与公共数据集整合在一起。对于非癌性乳腺组织，炎症、上皮-间充质转化 (EMT) 和雌激素反应途径显示出昼夜节律的调节。在肿瘤中，时钟相关性分析表明昼夜节律组织发生了特定于亚型的变化。腔 A 类器官和腔 A 样本的信息学排序显示出持续的、尽管减弱和重新编程的节律。然而，CYCLOPS 幅度，衡量全局节律强度的指标，在腔 A 样本中差异很大。高幅度腔 A 肿瘤中 EMT 途径基因的循环明显增加。令人惊讶的是，具有高幅度肿瘤的患者 5 年生存率降低。相应地，3D 腔 A 培养物在分子时钟中断后显示出侵袭性降低。这项研究将乳腺癌中特定于亚型的昼夜节律紊乱与 EMT、转移潜力和预后联系起来。
