DAXX, as a Tumor Suppressor, Impacts DNA Damage Repair and Sensitizes BRCA-Proficient TNBC Cells to PARP Inhibitors
DAXX, as a Tumor Suppressor, Impacts DNA Damage Repair and Sensitizes BRCA-Proficient TNBC Cells to PARP Inhibitors
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DAXX 作为肿瘤抑制剂，影响 DNA 损伤修复并使 BRCA 熟练的 TNBC 细胞对 PARP 抑制剂敏感
DOI：
10.1016/j.neo.2019.04.001
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发表时间：
2019-06-01
期刊：
影响因子：
4.8
通讯作者：
Guan, Xiaoxiang
中科院分区：
文献类型：
--
作者：
Shi, Yaqin;Jin, Juan;Guan, Xiaoxiang
三阴性乳腺癌（TNBC）患者的治疗选择有限。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。DAXX是一种死亡结构域相关蛋白，据报道在多种癌症类型的癌症进展和药物敏感性中起关键作用。然而，它在乳腺癌，尤其是TNBC中的作用仍不清楚。在这里，我们证明了DAXX在TNBC增殖、集落形成和迁移中的抑瘤功能。在小鼠异种移植模型中，DAXX显著抑制TNBC细胞的致瘤性。在机制上，DAXX可以直接结合到RAD51的启动子区域，阻碍DNA损伤修复，从而影响肿瘤细胞的保护机制，而肿瘤细胞的生长很大程度上依赖于剩余的DDR通路。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RI-1和ABT888对RAD51和PARP的双重抑制在体外和体内都显著降低了TNBC的生长，这为brca精通的TNBC提供了RAD51和PARP联合抑制的第一个证据。总之，我们的数据支持DAXX作为DNA损伤修复的调节剂和TNBC进展的抑制因子，通过抑制RAD51的功能使肿瘤对PARP抑制剂敏感。这为更好地应用PARP抑制治疗TNBC提供了一种有效的策略。
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.