三阴性乳腺癌（TNBC）是乳腺癌的一种亚型，与转移、高复发率和低生存率相关。基本的螺旋-环-螺旋转录因子 SHARP1（分裂和毛相关蛋白 1）已被确定为 TNBC 转移行为的抑制因子。 SHARP1 通过抑制缺氧诱导因子来阻断 TNBC 的侵袭表型，其缺失与乳腺癌患者的较差生存率相关。在这里，我们证明 SHARP1 是一种不稳定的蛋白质，它是 E3 泛素连接酶复合物 SCFβTrCP 蛋白酶体降解的目标。 SHARP1 通过包含 Ser240 和 Glu245 的磷酸化降解子招募 βTrCP，这是 SHARP1 泛素化和降解所必需的。此外，注射表达不可降解SHARP1（S240A/E245A）突变体的TNBC细胞的小鼠显示出肿瘤生长减少和无肿瘤生存增加。我们的研究表明，针对 SHARP1 的 βTrCP 依赖性降解是 TNBC 的一种治疗策略。© 2023。作者。

Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with metastasis, high recurrence rate, and poor survival. The basic helix-loop-helix transcription factor SHARP1 (Split and Hairy-related Protein 1) has been identified as a suppressor of the metastatic behavior of TNBC. SHARP1 blocks the invasive phenotype of TNBC by inhibiting hypoxia-inducible factors and its loss correlates with poor survival of breast cancer patients. Here, we show that SHARP1 is an unstable protein that is targeted for proteasomal degradation by the E3 ubiquitin ligase complex SCFβTrCP. SHARP1 recruits βTrCP via a phosphodegron encompassing Ser240 and Glu245 which are required for SHARP1 ubiquitylation and degradation. Furthermore, mice injected with TNBC cells expressing the non-degradable SHARP1(S240A/E245A) mutant display reduced tumor growth and increased tumor-free survival. Our study suggests that targeting the βTrCP-dependent degradation of SHARP1 represents a therapeutic strategy in TNBC.© 2023. The Author(s).