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PICH缺失促进三阴性乳腺癌染色体不稳定性和细胞死亡
三阴性乳腺癌(TNBC)的定义是缺乏雌激素,孕激素和ERBB2受体,在所有乳腺癌中预后最差。由于缺乏有效的分子靶标而难以治疗。在这里,我们报道TNBC细胞的生长异常依赖于PICH,一种依赖DNA的ATPase。临床样本分析表明,与其他乳腺癌亚型相比,PICH在TNBC中高表达。重要的是,其高表达与远端转移的较高风险和较差的临床结果相关。进一步的分析表明,在体外和体内,PICH的消耗选择性地损害TNBC细胞的增殖,但不损害管腔乳腺癌细胞的增殖。此外,在TNBC细胞中敲除PICH会导致后期形成染色质桥和落后的染色体,经常导致微核或双核,最终导致有丝分裂灾难和细胞凋亡。总的来说,我们的研究结果表明TNBC细胞对PICH的忠实染色体分离具有依赖性,并具有抑制PICH的临床潜力以改善高危TNBC患者的治疗。**
Loss of PICH promotes chromosome instability and cell death in triple-negative breast cancer
Triple-negative breast cancer (TNBC), defined by the lack of expression of estrogen, progesterone, and ERBB2 receptors, has the worst prognosis of all breast cancers. It is difficult to treat owing to a lack of effective molecular targets. Here, we report that the growth of TNBC cells is exceptionally dependent on PICH, a DNA-dependent ATPase. Clinical samples analysis showed that PICH is highly expressed in TNBC compared to other breast cancer subtypes. Importantly, its high expression correlates with higher risk of distal metastasis and worse clinical outcomes. Further analysis revealed that PICH depletion selectively impairs the proliferation of TNBC cells, but not that of luminal breast cancer cells, in vitro and in vivo. In addition, knockdown of PICH in TNBC cells induces the formation of chromatin bridges and lagging chromosomes in anaphase, frequently resulting in micronucleation or binucleation, finally leading to mitotic catastrophe and apoptosis. Collectively, our findings show the dependency of TNBC cells on PICH for faithful chromosome segregation and the clinical potential of PICH inhibition to improve treatment of patients with high-risk TNBC.
pmid: 31160555 Cell Death Dis 影响因子: 5.959 发表日期: 20190603 官网 免费下载
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