肿瘤细胞转移到远处器官后，通常会受远处微环境的抑制而产生近乎休眠的生长停滞。相比其它乳腺癌亚型，三阴性乳腺癌（TNBC）具有明显的早期转移特性，提示了TNBC具有逃逸休眠的能力；然而，其机制仍不清楚。近期，我们发现TNBC细胞由于基因扩增或者低氧诱导而特异高表达RIPK4激酶。进一步预实验结果显示：① RIPK4可通过磷酸化c-Myc而稳定其表达，解除TGF-β介导的肿瘤细胞生长停滞；② 同时，RIPK4可激活Wnt/β-Catenin和NOTCH信号通路，增强TNBC的肿瘤起始能力--干细胞样特性；③ 最终，RIPK4诱导TNBC细胞在远处器官的休眠逃逸，活化细胞并促进宏观转移灶的形成。然而，其详细的分子机制仍有待阐明。本项目将承前启后，深层次解析RIPK4激酶介导TNBC休眠逃逸的分子机制，为肿瘤转移提供新的理论依据；同时，与临床研究相结合，探讨RIPK4激酶在TNBC诊治中的意义。

Disseminated tumor cells often suffer an unfamiliar repressive microenvironment and kept dormant in distant organs. Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and has a characteristic pattern of early metastasis, indicating that TNBC has high ability to escape from tumor dormancy; however, the mechanism remains unclear. Recently, we found that Receptor-interacting serine/threonine-protein kinase 4 (RIPK4) was specifically expressed in TNBC cells via gene amplification and hypoxia induction. Furthermore, we observed that: ① RIPK4 could abrogate the TGF-β-mediated cell cycle arrest via stabilization of c-Myc; ② Meanwhile, RIPK4 increased the cancer stem cell like-properties by simultaneous activation of Wnt/β-Catenin and NOTCH signaling pathways in TNBC; ③ Thus, RIPK4 was able to induce escape from dormancy and reactivate TNBC cells in distant organs, resulting in formation of overt metastases. In this project, we will combine both in vitro and in vivo experiment systems, as well as analysis of clinical samples, in order to investigate the pleiotropic functions of RIPK4 in TNBC distant colonization. Our work would provide novel prognostic markers and therapeutic targets against TNBC.