Triple-negative breast cancers (TNBC) frequently harbor defects in DNA double-strand break repair through homologous recombination (HR), such as BRCA1 dysfunction. However, less than 15% of TNBC patients were found to carry BRCA1 mutation, indicating that there are other mechanisms regulating BRCA1-deficient in TNBC. In the current study, we shown that overexpression of TRIM47 correlates with progression and poor prognosis in triple-negative breast cancer. Moreover, we demonstrated that TRIM47 directly interacts with BRCA1 and induces ubiquitin-ligase-mediated proteasome turnover of BRCA1, subsequently leads to a decrease of BRCA1 protein levels in TNBC. Moreover, the downstream gene expression of BRCA1, such as p53, p27, p21 was significantly reduced in the overexpression of TRIM47 cell lines but increased in TRIM47-deleted cells. Functionally, we found that overexpression of TRIM47 in TNBC cells confers an exquisite sensitivity to olaparib, an inhibitor of poly-(ADP-ribose)-polymerase (PARP), but TRIM47 inhibition significantly confers TNBC cells resistance to olaparib both in vitro and in vivo. Furthermore, we showed that overexpression of BRCA1 significant increase the olaparib resistance in TRIM47-overexpression-induced PARP inhibitions sensitivity. Taken together, our results uncover a novel mechanism for BRCA1-deficient in TNBC and targeting TRIM47/BRCA1 axis may be a promising prognostic factor and a valuable therapeutic target for TNBC.

三阴性乳腺癌 (TNBC) 通过同源重组 (HR) 在 DNA 双链断裂修复中经常存在缺陷，例如 BRCA1 功能障碍。然而，只有不到 15% 的 TNBC 患者被发现携带 BRCA1 突变，这表明在 TNBC 中存在调节 BRCA1 缺陷的其他机制。在当前的研究中，我们表明 TRIM47 的过表达与三阴性乳腺癌的进展和不良预后相关。此外，我们证明 TRIM47 直接与 BRCA1 相互作用并诱导泛素连接酶介导的 BRCA1 蛋白酶体转换，随后导致 TNBC 中 BRCA1 蛋白水平的降低。此外，BRCA1 的下游基因表达，如 p53、p27、p21，在 TRIM47 细胞系的过表达中显着降低，但在 TRIM47 缺失的细胞中表达增加。在功能上，我们发现 TNBC 细胞中 TRIM47 的过表达赋予奥拉帕尼极佳的敏感性，奥拉帕尼是聚（ADP-核糖）聚合酶 (PARP) 的抑制剂，但 TRIM47 抑制显着赋予 TNBC 细胞在体外和体内对奥拉帕尼的耐药性。此外，我们发现 BRCA1 的过表达显着增加了 TRIM47 过表达诱导的 PARP 抑制敏感性中的奥拉帕尼抗性。综上所述，我们的结果揭示了 TNBC 中 BRCA1 缺陷的新机制，靶向 TRIM47/BRCA1 轴可能是 TNBC 的一个有前途的预后因素和有价值的治疗靶点。但 TRIM47 抑制显着赋予 TNBC 细胞对奥拉帕尼的体外和体内耐药性。此外，我们发现 BRCA1 的过表达显着增加了 TRIM47 过表达诱导的 PARP 抑制敏感性中的奥拉帕尼抗性。综上所述，我们的结果揭示了 TNBC 中 BRCA1 缺陷的新机制，靶向 TRIM47/BRCA1 轴可能是 TNBC 的一个有前途的预后因素和有价值的治疗靶点。但 TRIM47 抑制显着赋予 TNBC 细胞对奥拉帕尼的体外和体内耐药性。此外，我们发现 BRCA1 的过表达显着增加了 TRIM47 过表达诱导的 PARP 抑制敏感性中的奥拉帕尼抗性。综上所述，我们的结果揭示了 TNBC 中 BRCA1 缺陷的新机制，靶向 TRIM47/BRCA1 轴可能是 TNBC 的一个有前途的预后因素和有价值的治疗靶点。