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首页> 外文期刊>Cell cycle >A novel crosstalk between BRCA1 and poly (ADP-ribose) polymerase 1 in breast cancer
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A novel crosstalk between BRCA1 and poly (ADP-ribose) polymerase 1 in breast cancer

机译：乳腺癌中BRCA1与聚（ADP-核糖）聚合酶1之间的新型串扰

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BRCA mutations are the main known hereditary factor for breast cancer. Notably, poly (ADP-ribose) polymerase 1 (PARP1) expression status plays a critical role in breast cancer progression and the clinical development of PARP1 inhibitors to treat BRCA-mutated breast cancer has advanced rapidly. However, dynamic crosstalk between BRCA1 and PARP1 remains largely unknown. Here, we showed that: (i) BRCA1 inactivation events (mutation, promoter methylation, or knockdown) were accompanied by increased PARP1 and nicotinamide adenine dinucleotide (NAD) levels, and a subsequent increase in NAD-dependent PARP1 activity in MDA-MB-231 and primary breast cancer cells; (ii) the overexpression of BRCA1 resulted in decreased PARP1 and NAD levels, and a subsequent impairment in NAD-dependent PARP1 activity in MDA-MB-231 and primary breast cancer cells; and (iii) intracellular NAD levels were largely responsible for regulating PARP1 activity in breast cancer cells, and NAD levels were positively correlated with PARP1 activity in human breast cancer specimens (R = 0.647, P < 0.001). Interestingly, the high efficiency of PARP1 triggered by BRCA1 inactivation may further inhibit BRCA1 transcription by NAD depletion. These results highlight a novel interaction between BRCA1 and PARP1, which may be beneficial for the dynamic balance between BRCA1 and PARP1-related biologic processes, especially for maintaining stable DNA repair ability. All of this may improve our understanding of the basic molecular mechanism underlying BRCA1- and PARP1-related breast cancer progression.
机译：BRCA突变是乳腺癌的主要已知遗传因素。值得注意的是，聚（ADP-核糖）聚合酶1（PARP1）的表达状态在乳腺癌的进展中起着至关重要的作用，而用于治疗BRCA突变型乳腺癌的PARP1抑制剂的临床开发也在迅速发展。但是，BRCA1和PARP1之间的动态串扰仍然未知。在这里，我们表明：（i）BRCA1失活事件（突变，启动子甲基化或敲低）伴随着PARP1和烟酰胺腺嘌呤二核苷酸（NAD）水平的升高，以及随后MDA-MB-中NAD依赖性PARP1活性的升高。 231和原发性乳腺癌细胞; （ii）BRCA1的过度表达导致MARP-MB-231和原发性乳腺癌细胞中PARP1和NAD水平降低，并随后损害NAD依赖性PARP1活性; （iii）细胞内NAD水平在很大程度上调节了乳腺癌细胞中PARP1的活性，而NAD水平与人乳腺癌样品中PARP1的活性呈正相关（R = 0.647，P <0.001）。有趣的是，BRCA1失活触发的PARP1的高效率可能进一步抑制了NAD耗竭的BRCA1转录。这些结果突出了BRCA1和PARP1之间的新型相互作用，这可能有利于BRCA1和PARP1相关的生物过程之间的动态平衡，尤其是保持稳定的DNA修复能力。所有这些可能会增进我们对BRCA1和PARP1相关乳腺癌进展的基本分子机制的了解。

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