三阴性乳腺癌（TNBC）缺乏已知治疗靶点、预后较差，是乳腺癌治疗的难点。最新研究显示TNBC可进一步分为6个亚型，其中间质干细胞样（MSL）型有肿瘤干细胞特性，不仅抵抗化疗且易于增殖侵袭，是导致整组TNBC预后差的重要原因。我们前期研究和预实验发现：趋化因子诱骗受体DARC通过清除多种趋化因子抑制乳腺癌增殖转移；DARC还能有效降低微环境中CCL28浓度；而CCL28不仅在MSL型TNBC中高表达，也是复发转移的风险因素。由此，我们提出下一步研究假设：DARC可通过清除CCL28来抑制MSL型TNBC的增殖转移。本课题是在上个青年项目基础上的深入（从一般性乳腺癌聚焦到TNBC）与创新（探讨DARC-CCL28新通路），成果将确立MSL型TNBC易于增殖侵袭、预后不良的生物学基础，并为寻找其治疗策略提供参考。申请人已基本完成上个项目的任务，以第一作者发表标注自然基金资助的SCI论著11篇。

Triple-negative breast cancer (TNBC), defined by the lack of expression of ER, PR, and the absence of amplification or over-expression of HER2, lacks known druggable targets and presents with relatively poor survival compared with other subtypes. Recently, six TNBC subtypes have been identified and one of them is a mesenchymal stem-like (MSL) subtype, which is heavily enriched in components and pathways involved in cancer stem cell. MSL subtype is demonstrated to be chemoresistant and has highly proliferative and invasive potential, which is the major cause of poor prognosis of general TNBC. Our previous investigations and preliminary experiments have demonstrated that, the inhibitory effect of the chemokine decoy receptor DARC on breast cancer growth and metastasis is mainly due to its ability to sequester pro-malignant chemokines. Furthermore, DARC could effectively decrease the concentration of CCL28, which is specifically up-regulated in MSL subtype and a higher expression of CCL28 is associated with significantly increased risk of relapse of TNBC. Taken together, we here propose a hypothesis that chemokine decoy receptor DARC could inhibit growth and invasion of the MSL subtype of TNBC via sequestrating CCL28 in tumor microenvironment. This project is based on the our previous Young Project of National Natural Science Foundation of China. The outcomes would be helpful to understand the biological basis of the aggressive behavior of MSL subtype and to find the treatment strategy for this subtype. The applicant has completed the tasks in the previous Young Project and has published 11 SCI papers of relevant achievement supported by the grant.