Gain-of-Function Mutant p53 R273H Interacts with Replicating DNA and PARP1 in Breast Cancer
Gain-of-Function Mutant p53 R273H Interacts with Replicating DNA and PARP1 in Breast Cancer
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DOI：
10.1158/0008-5472.can-19-1036
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发表时间：
2020-02-01
期刊：
影响因子：
11.2
通讯作者：
Bargonetti, Jill
中科院分区：
文献类型：
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作者：
Xiao, Gu;Lundine, Devon;Bargonetti, Jill
超过80%的三阴性乳腺癌(TNBC)表达突变型P53(MtP53)，部分表达癌基因增强功能(GOF)P53。我们以前报道过GOF mtp53 R273H上调小染色体维护(MCM)蛋白MCM2-7和PARP的染色质结合，并将其命名为mtp53-PARP-MCM轴。在这项研究中，我们使用了许多不同的细胞系、患者来源的异种移植(PDX)、组织芯片(TMA)和癌症基因组图谱(TCGA)数据库，剖析了mtp53和PARP之间的功能和联系。内源性mtp53 R273H和外源表达R273H和R248W结合新生的5-乙炔-2‘-脱氧尿嘧啶核苷标记的复制DNA。增加mtp53 R273H可增强mtp53与PARP在复制DNA上的结合。阻断聚腺苷二磷酸核糖糖水解酶也加强了这种联系。此外，mtp53 R273H的表达增加了MCM2的总体水平，促进了细胞的增殖，并改善了烷化剂替莫唑胺与PARP抑制剂(PARPI)他唑帕利联合处理的协同细胞毒性。P53和PARP1在乳腺癌TMAS中的表达及与TCGA数据库的比较显示，基底细胞样癌的双阳性信号高于腔A或腔B亚型。与野生型P53表达的PDX相比，mtP53 R273H中的PARP1蛋白和PAR蛋白水平更高。这些结果表明，mtp53被认为是识别可能对PARPI联合治疗有反应的乳腺癌的双重生物标记物。意义：P53功能获得突变体273H和PARP1与复制叉相互作用，可能成为乳腺癌对PARP抑制剂敏感性的潜在生物标记物。
Over 80% of triple-negative breast cancers (TNBC) express mutant p53 (mtp53) and some contain oncogenic gain-offunction (GOF) p53. We previously reported that GOF mtp53 R273H upregulates the chromatin association of mini chromosome maintenance (MCM) proteins MCM2-7 and PARP and named this the mtp53-PARP-MCM axis. In this study, we dissected the function and association between mtp53 and PARP using a number of different cell lines, patient-derived xenografts (PDX), tissue microarrays (TMA), and The Cancer Genome Atlas (TCGA) database. Endogenous mtp53 R273H and exogenously expressed R273H and R248W bound to nascent 5-ethynyl-2'-deoxyuridine-labeled replicating DNA. Increased mtp53 R273H enhanced the association of mtp53 and PARP on replicating DNA. Blocking poly-ADP-ribose gylcohydrolase also enhanced this association. Moreover, mtp53 R273H expression enhanced overall MCM2 levels, promoted cell proliferation, and improved the synergistic cytotoxicity of treatment with the alkylating agent temozolomide in combination with the PARP inhibitor (PARPi) talazoparib. Staining of p53 and PARP1 in breast cancer TMAs and comparison with the TCGA database indicated a higher double-positive signal in basal-like breast cancer than in luminal A or luminal B subtypes. Higher PARP1 protein levels and PAR proteins were detected in mtp53 R273H than in wildtype p53-expressing PDX samples. These results indicate that mtp53 considered as dual biomarkers for identifying breast cancers that may respond to combination PARPi treatments.Significance: p53 gain-of-function mutant 273H and PARP1 interact with replication forks and could serve as potential biomarkers for breast cancer sensitivity to PARP inhibitors.[GRAPHICS].