A novel crosstalk between BRCA1 and poly (ADP-ribose) polymerase 1 in breast cancer

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, <i>P</i> &lt; 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.

BRCA突变是目前已知的乳腺癌主要遗传致病因素。值得关注的是，聚（ADP-核糖）聚合酶1（poly (ADP-ribose) polymerase 1, PARP1）的表达状态在乳腺癌进展过程中发挥关键调控作用，针对BRCA突变型乳腺癌的PARP1抑制剂临床研发亦进展迅猛。然而，BRCA1与PARP1之间的动态串扰机制目前仍尚未完全阐明。本研究证实：（1）在MDA-MB-231细胞及原代乳腺癌细胞中，BRCA1失活事件（涵盖突变、启动子甲基化或基因敲低）会伴随PARP1与烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD）水平升高，并随之出现依赖于NAD的PARP1活性增强；（2）在上述细胞系中，BRCA1过表达则会导致PARP1与NAD水平下调，并削弱依赖于NAD的PARP1活性；（3）细胞内NAD水平是调控乳腺癌细胞PARP1活性的核心因素，且在人类乳腺癌组织标本中，NAD水平与PARP1活性呈显著正相关（R=0.647，P<0.001）。有趣的是，BRCA1失活所触发的PARP1高活性，可能通过消耗NAD进一步抑制BRCA1的转录。本研究结果揭示了BRCA1与PARP1之间一种全新的相互作用模式，该相互作用或有助于维持BRCA1与PARP1相关生物学过程的动态平衡，尤其对维持稳定的DNA修复能力具有重要意义。上述发现或可增进我们对BRCA1及PARP1相关乳腺癌进展的核心分子机制的理解。