三阴性乳腺癌 (TNBC) 是一种异质性乳腺癌亚型，约占乳腺癌病例的 15-20%。在这项研究中，我们确定了 KLHL29（Kelch 样基因家族的一个尚未研究的成员）是调节 TNBC 化疗敏感性的重要肿瘤抑制因子。与癌旁正常组织相比，乳腺癌组织中KLHL29的表达显着下调，且低水平的KLHL29与不良预后相关。异位KLHL29抑制TNBC的生长、增殖、迁移和侵袭，而耗尽KLHL29则促进TNBC的生长、增殖、迁移和侵袭。从机制上讲，KLHL29 将 CUL3 E3 连接酶招募到 RNA 结合蛋白 DDX3X 上，导致后者被蛋白酶体降解。 DDX3X 的下调导致 CCND1 mRNA 不稳定，并随后导致细胞周期停滞在 G0/G1 期。值得注意的是，使用癌细胞来源的异种移植物和患者来源的类器官模型，DDX3X抑制剂RK33与铂类化疗联合可以协同抑制通常表达低水平KLHL29和高水平DDX3X的TNBC。总之，我们发现了 KLHL29-DDX3X 信号级联在调节 TNBC 进展中的潜在作用，从而为克服 TNBC 化疗耐药性提供了一种有前途的组合策略。© 2023。作者。

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype and accounts for approximately 15-20% of breast cancer cases. In this study, we identified KLHL29, which is an understudied member of the Kelch-like gene family, as a crucial tumor suppressor that regulates chemosensitivity in TNBC. KLHL29 expression was significantly downregulated in breast cancer tissues compared with adjacent normal tissues, and low levels of KLHL29 were associated with unfavorable prognoses. Ectopic KLHL29 suppressed, while depleting KLHL29 promoted, the growth, proliferation, migration, and invasion of TNBC. Mechanistically, KLHL29 recruited the CUL3 E3-ligase to the RNA-binding protein DDX3X, leading to the proteasomal degradation of the latter. This downregulation of DDX3X resulted in the destabilization of CCND1 mRNA and the consequent cell cycle arrest at G0/G1 phase. Remarkably, the DDX3X inhibitor RK33 combined with platinum-based chemotherapy can synergistically suppress TNBC that usually expresses low levels of KLHL29 and high levels of DDX3X using cancer cell-derived xenograft and patient-derived organoids models. Altogether, we uncovered the potential role for the KLHL29-DDX3X signaling cascade in the regulation of TNBC progression, thus providing a promising combination strategy for overcoming TNBC chemoresistance.© 2023. The Author(s).