PI3K-AKT信号通路在癌症中经常出现异常，并且在约50％的乳腺癌患者中，该通路过度活化。虽然已经开发了直接靶向PI3K-AKT轴的抑制剂，但临床疗效仅限于少数患者。识别引发AKT驱动的肿瘤发生机制可能会导致替代方法来阻断通路信号并抑制乳腺肿瘤生长。质谱分析表明，盐诱导激酶1（SIK1）与AKT结合并经受AKT介导的磷酸化，从而破坏SIK1的抑制肿瘤功能。因此，AKT通过磷酸化依赖性的方式解除了SIK1对STAT3的结合和抑制，导致了乳腺细胞肿瘤发生。在AKT介导的磷酸化之后，SIK1与14-3-3相互作用，并被转移到了细胞质，在那里畸变酶Pin1促进了SIK1与E3连接酶ITCH的相互作用，以促进SIK1的泛素化和随后的降解。这些发现表明，SIK1是AKT的底物，它将AKT的致癌功能与STAT3的激活联系起来，突出了靶向JAK2-STAT3轴作为治疗AKT驱动乳腺癌策略的重要性。

The PI3K-AKT signaling pathway is frequently dysregulated in cancer, and it is hyperactivated in approximately 50% of breast cancers. While inhibitors directly targeting the PI3K-AKT axis have been developed, clinical efficacy has been limited to only a subset of patients. Identification of mechanisms underlying AKT-driven tumorigenesis could lead to alternative approaches to block pathway signaling and suppress breast tumor growth. Mass spectrometry-based analyses demonstrated that salt-inducible kinase 1 (SIK1) binds AKT and undergoes AKT-mediated phosphorylation, which compromises SIK1 tumor-suppressive functions. As a result, AKT relieved the binding and repression of STAT3 by SIK1 in a phosphorylation-dependent manner, resulting in breast cell tumorigenesis. Following AKT-mediated phosphorylation, SIK1 interacted with 14-3-3 and was translocated to the cytoplasm where the isomerase Pin1 facilitated SIK1 interaction with the E3 ligase ITCH to promote SIK1 ubiquitination and subsequent degradation. These findings indicate that SIK1 is a substrate of AKT that links AKT oncogenic function to STAT3 activation, highlighting targeting of the JAK2-STAT3 axis as a strategy to treat AKT-driven breast cancer.