Cancer Research Center of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Léon Bérard Cancer Centre, Cheney A, 28 rue Laennec, 69373 cedex 08, Lyon, France.
Institut Convergence PLAsCAN, 69373 cedex 08, Lyon, France.
BMC Cancer. 2022 May 11;22(1):526. doi: 10.1186/s12885-022-09552-x.
A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated.
Here, fibrillarin (FBL) was used as a surrogate marker of ribosome biogenesis due to its essential role in the early steps of ribosome biogenesis and its association with poor prognosis in breast cancer when overexpressed. Using 3,275 non-metastatic primary breast tumors, we analysed FBL mRNA expression levels and protein nucleolar organisation. Usage of TCGA dataset allowed transcriptomic comparison between the different FBL expression levels-related breast tumours.
We unexpectedly discovered that in addition to breast tumours expressing high level of FBL, about 10% of the breast tumors express low level of FBL. A correlation between low FBL mRNA level and lack of FBL detection at protein level using immunohistochemistry was observed. Interestingly, multivariate analyses revealed that these low FBL tumors displayed poor outcome compared to current clinical gold standards. Transcriptomic data revealed that FBL expression is proportionally associated with distinct amount of ribosomes, low FBL level being associated with low amount of ribosomes. Moreover, the molecular programs supported by low and high FBL expressing tumors were distinct.
Altogether, we identified FBL as a powerful ribosome biogenesis-related independent marker of breast cancer outcome. Surprisingly we unveil a dual association of the ribosome biogenesis FBL factor with prognosis. These data suggest that hyper- but also hypo-activation of ribosome biogenesis are molecular traits of distinct tumors.
目前，在早期乳腺癌中鉴定预后和预测标志物仍然是一个关键需求。似乎癌细胞的一个显著特征是它们对核糖体生物发生的过度激活上瘾。因此，核糖体生物发生可能是一个有待评估的创新生物标志物来源。
在这里，由于其在核糖体生物发生的早期步骤中的重要作用及其与乳腺癌中过度表达时预后不良的关联，使用核仁蛋白（FBL）作为核糖体生物发生的替代标志物。使用 3275 例非转移性原发性乳腺癌肿瘤，我们分析了 FBL mRNA 表达水平和核仁组织。使用 TCGA 数据集允许对不同 FBL 表达水平相关的乳腺癌肿瘤进行转录组比较。
我们意外地发现，除了表达高水平 FBL 的乳腺癌肿瘤外，约 10%的乳腺癌肿瘤表达低水平的 FBL。观察到 FBL mRNA 水平低与使用免疫组织化学法在蛋白质水平上检测到的 FBL 缺乏之间存在相关性。有趣的是，多变量分析显示，与当前的临床金标准相比，这些低 FBL 肿瘤的预后较差。转录组数据显示，FBL 表达与核糖体的数量成正比，低 FBL 水平与核糖体的数量低有关。此外，低 FBL 和高 FBL 表达肿瘤支持的分子程序是不同的。
总之，我们将 FBL 鉴定为一种强大的与乳腺癌预后相关的核糖体生物发生相关的独立标志物。令人惊讶的是，我们揭示了核糖体生物发生 FBL 因子与预后的双重关联。这些数据表明，核糖体生物发生的过度激活和低激活都是不同肿瘤的分子特征。
