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首页> 外文期刊>Neoplasia: an international journal for oncology research >DAXX, as a Tumor Suppressor, Impacts DNA Damage Repair and Sensitizes BRCA-Proficient TNBC Cells to PARP Inhibitors 1
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DAXX, as a Tumor Suppressor, Impacts DNA Damage Repair and Sensitizes BRCA-Proficient TNBC Cells to PARP Inhibitors 1

机译：DAXX作为一种肿瘤抑制物，影响DNA损伤修复，并使BRCA熟练的TNBC细胞对PARP抑制剂敏感 1

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Treatment options are limited for patients with triple negative breast cancer (TNBC). Understanding genes that participate in cancer progression and DNA damage response (DDR) may improve therapeutic strategies for TNBC. DAXX, a death domain-associated protein, has been reported to be critically involved in cancer progression and drug sensitivity in multiple cancer types. However, its role in breast cancer, especially for TNBC, remains unclear. Here, we demonstrated a tumor suppressor function of DAXX in TNBC proliferation, colony formation, and migration. In Mouse Xenograft Models, DAXX remarkably inhibited tumorigenicity of TNBC cells. Mechanistically, DAXX could directly bind to the promoter region of RAD51 and impede DNA damage repair, which impacted the protection mechanism of tumor cells that much depended on remaining DDR pathways for cell growth. Furthermore, DAXX-mediated inefficient DNA damage repair could sensitize BRCA-proficient TNBC cells to PARP inhibitors. Additionally, we identified that dual RAD51 and PARP inhibition with RI-1 and ABT888 significantly reduced TNBC growth both in vitro and in vivo , which provided the first evidence of combining RAD51 and PARP inhibition in BRCA-proficient TNBC. In conclusion, our data support DAXX as a modulator of DNA damage repair and suppressor of TNBC progression to sensitize tumors to the PARP inhibitor by repressing RAD51 functions. These provide an effective strategy for a better application of PARP inhibition in the treatment of TNBC.
机译：对于三阴性乳腺癌（TNBC）的患者，治疗选择有限。了解参与癌症进展和DNA损伤反应（DDR）的基因可能会改善TNBC的治疗策略。据报道，DAXX是一种与死亡域相关的蛋白质，在多种癌症类型中都与癌症进展和药物敏感性密切相关。但是，其在乳腺癌中的作用，特别是对于TNBC，尚不清楚。在这里，我们证明了DAXX在TNBC增殖，集落形成和迁移中具有抑癌功能。在小鼠异种移植模型中，DAXX显着抑制TNBC细胞的致瘤性。从机理上讲，DAXX可以直接结合到RAD51的启动子区域，并阻碍DNA损伤修复，这影响了肿瘤细胞的保护机制，而该机制在很大程度上依赖于其余的DDR途径来促进细胞生长。此外，DAXX介导的低效率DNA损伤修复可以使BRCA精通的TNBC细胞对PARP抑制剂敏感。此外，我们发现用RI-1和ABT888双重抑制RAD51和PARP会显着降低体内和体外TNBC的生长，这提供了将RAD51和PARP抑制结合在BRCA熟练的TNBC中的第一个证据。总之，我们的数据支持DAXX作为DNA损伤修复的调节剂和TNBC进程的抑制剂，通过抑制RAD51的功能使肿瘤对PARP抑制剂敏感。这些为更好地应用PARP抑制治疗TNBC提供了有效的策略。

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