Rieckhoff Johanna, Meyer Felix, Classen Sandra, Zielinski Alexandra, Riepen Britta, Wikman Harriet, Petersen Cordula, Rothkamm Kai, Borgmann Kerstin, Parplys Ann Christin
Laboratory of Radiobiology & Experimental Radio Oncology, Centre of Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Department of Tumor Biology, Center of Experimental Medicine, University Medical Center, Hamburg-Eppendorf, 20246 Hamburg, Germany.
Cancers (Basel). 2020 Sep 29;12(10):2809. doi: 10.3390/cancers12102809.
Chromosomal instability (CIN) is an emerging hallmark of cancer and its role in therapeutic responses has been increasingly attracting the attention of the research community. To target the vulnerability of tumors with high CIN, it is important to identify the genes and mechanisms involved in the maintenance of CIN. In our work, we recognize the tumor suppressor gene Phosphatase and Tensin homolog ( as a potential gene causing CIN in triple-negative breast cancer (TNBC) and show that TNBC with low expression levels of PTEN can be sensitized for the treatment with poly-(ADP-ribose)-polymerase 1 (PARP1) inhibitors, independent of Breast Cancer (BRCA) mutations or a BRCA-like phenotype. In silico analysis of mRNA expression data from 200 TNBC patients revealed low expression of PTEN in tumors with a high CIN70 score. Western blot analysis of TNBC cell lines confirm lower protein expression of PTEN compared to non TNBC cell lines. Further, PTEN-deficient cell lines showed cellular sensitivity towards PARP1 inhibition treatment. DNA fiber assays and examination of chromatin bound protein fractions indicate a protective role of PTEN at stalled replication forks. In this study, we recognize as a potential CIN-causing gene in TNBC and identify its important role in the replication processes.
染色体不稳定（CIN）是癌症新出现的一个特征，其在治疗反应中的作用越来越受到研究界的关注。为了针对具有高CIN的肿瘤的脆弱性，识别参与维持CIN的基因和机制很重要。在我们的研究中，我们认识到肿瘤抑制基因磷酸酶和张力蛋白同源物（PTEN）是三阴性乳腺癌（TNBC）中导致CIN的一个潜在基因，并表明PTEN低表达水平的TNBC对聚（ADP - 核糖）聚合酶1（PARP1）抑制剂治疗敏感，这与乳腺癌（BRCA）突变或BRCA样表型无关。对200例TNBC患者的mRNA表达数据进行的计算机分析显示，在CIN70评分高的肿瘤中PTEN表达较低。对TNBC细胞系的蛋白质免疫印迹分析证实，与非TNBC细胞系相比，PTEN的蛋白质表达更低。此外，PTEN缺陷的细胞系对PARP1抑制治疗表现出细胞敏感性。DNA纤维分析和对染色质结合蛋白组分的检测表明PTEN在停滞的复制叉处具有保护作用。在本研究中，我们认识到PTEN是TNBC中一个潜在的导致CIN的基因，并确定了其在复制过程中的重要作用。
