Wellcome Centre for Cell-Matrix Research and Manchester Breast Centre, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
Breast Cancer Res. 2018 Oct 22;20(1):125. doi: 10.1186/s13058-018-1053-4.
Circadian rhythms maintain tissue homeostasis during the 24-h day-night cycle. Cell-autonomous circadian clocks play fundamental roles in cell division, DNA damage responses and metabolism. Circadian disruptions have been proposed as a contributing factor for cancer initiation and progression, although definitive evidence for altered molecular circadian clocks in cancer is still lacking. In this study, we looked at circadian clocks in breast cancer.
We isolated primary tumours and normal tissues from the same individuals who had developed breast cancer with no metastases. We assessed circadian clocks within primary cells of the patients by lentiviral expression of circadian reporters, and the levels of clock genes in tissues by qPCR. We histologically examined collagen organisation within the normal and tumour tissue areas, and probed the stiffness of the stroma adjacent to normal and tumour epithelium using atomic force microscopy.
Epithelial ducts were disorganised within the tumour areas. Circadian clocks were altered in cultured tumour cells. Tumour regions were surrounded by stroma with an altered collagen organisation and increased stiffness. Levels of Bmal1 messenger RNA (mRNA) were significantly altered in the tumours in comparison to normal epithelia.
Circadian rhythms are suppressed in breast tumour epithelia in comparison to the normal epithelia in paired patient samples. This correlates with increased tissue stiffness around the tumour region. We suggest possible involvement of altered circadian clocks in the development and progression of breast cancer.
昼夜节律在 24 小时的昼夜周期中维持组织内稳态。细胞自主的生物钟在细胞分裂、DNA 损伤反应和代谢中发挥着重要作用。昼夜节律紊乱被认为是癌症发生和进展的一个促成因素，尽管癌症中分子生物钟改变的确切证据仍然缺乏。在这项研究中，我们研究了乳腺癌中的生物钟。
我们从没有转移的乳腺癌患者身上分离出原发肿瘤和正常组织。我们通过慢病毒表达生物钟报告基因来评估患者原代细胞中的生物钟，并通过 qPCR 检测组织中的时钟基因水平。我们通过组织学检查正常和肿瘤组织区域内的胶原组织，并用原子力显微镜探测正常和肿瘤上皮细胞附近基质的硬度。
肿瘤区域内的上皮导管排列紊乱。培养的肿瘤细胞中的生物钟发生了改变。肿瘤区域被胶原组织改变和硬度增加的基质包围。与正常上皮相比，肿瘤中的 Bmal1 信使 RNA（mRNA）水平显著改变。
与配对患者样本中的正常上皮相比，乳腺癌上皮中的昼夜节律受到抑制。这与肿瘤区域周围组织硬度增加有关。我们推测，生物钟的改变可能参与了乳腺癌的发生和发展。
