Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon 1, Centre Léon Bérard, F-69008 Lyon, France.
Centre Léon Bérard, Medical Oncology Department, Université de Lyon 1, F-69008 Lyon, France.
Cells. 2020 Apr 10;9(4):941. doi: 10.3390/cells9040941.
BRCA1 inactivation is a hallmark of familial breast cancer, often associated with aggressive triple negative breast cancers. BRCA1 is a tumor suppressor with known functions in DNA repair, transcription regulation, cell cycle control, and apoptosis. In the present study, we demonstrate that BRCA1 is also a translational regulator. We previously showed that BRCA1 was implicated in translation regulation. Here, we asked whether translational control could be a novel function of BRCA1 that contributes to its tumor suppressive activity. A combination of RNA-binding protein immunoprecipitation, microarray analysis, and polysome profiling, was used to identify the mRNAs that were specifically deregulated under BRCA1 deficiency. Western blot analysis allowed us to confirm at the protein level the deregulated translation of a subset of mRNAs. A unique and dedicated cohort of patients with documented germ-line BRCA1 pathogenic variant statues was set up, and tissue microarrays with the biopsies of these patients were constructed and analyzed by immunohistochemistry for their content in each candidate protein. Here, we show that BRCA1 translationally regulates a subset of mRNAs with which it associates. These mRNAs code for proteins involved in major programs in cancer. Accordingly, the level of these key proteins is correlated with BRCA1 status in breast cancer cell lines and in patient breast tumors. ADAT2, one of these key proteins, is proposed as a predictive biomarker of efficacy of treatments recently recommended to patients with BRCA1 deficiency. This study proposes that translational control may represent a novel molecular mechanism with potential clinical impact through which BRCA1 is a tumor suppressor.
BRCA1 失活是家族性乳腺癌的一个标志，通常与侵袭性三阴性乳腺癌有关。BRCA1 是一种肿瘤抑制因子，具有已知的 DNA 修复、转录调控、细胞周期控制和细胞凋亡功能。在本研究中，我们证明 BRCA1 也是一种翻译调节因子。我们之前表明 BRCA1 参与翻译调节。在这里，我们想知道翻译控制是否可以是 BRCA1 的一种新功能，有助于其肿瘤抑制活性。我们使用 RNA 结合蛋白免疫沉淀、微阵列分析和多核糖体分析，鉴定在 BRCA1 缺陷下特异性失调的 mRNA。Western blot 分析使我们能够在蛋白质水平上证实一组 mRNA 的翻译失调。建立了一个具有明确记录的种系 BRCA1 致病性变异状态的独特且专门的患者队列，并构建了这些患者的组织微阵列，并通过免疫组织化学分析这些候选蛋白在每个患者中的含量。在这里，我们表明 BRCA1 翻译调节与其相关的一组 mRNA。这些 mRNA 编码参与癌症主要程序的蛋白质。因此，这些关键蛋白的水平与乳腺癌细胞系和患者乳腺肿瘤中的 BRCA1 状态相关。这些关键蛋白之一 ADAT2 被提议作为最近推荐给 BRCA1 缺陷患者的治疗效果的预测生物标志物。这项研究提出，翻译控制可能代表一种新的分子机制，通过这种机制，BRCA1 是一种肿瘤抑制因子，具有潜在的临床影响。
