乳腺癌干细胞（BCSCs）是三阴性乳腺癌复发的关键，其特性维持机制是肿瘤干细胞研究领域的瓶颈。申请人曾报道纤维鞘相互作用蛋白1（FSIP1）通过促进HER2蛋白胞内段络氨酸激酶的磷酸化调控乳腺癌的增殖，为乳腺癌治疗提供了新靶点（PNAS，2017）。预实验发现敲除FSIP1能促进三阴性乳腺癌中CD44-/CD24-细胞去分化为CD44+/CD24-BCSCs，伴随YAP/TAZ高表达。本研究拟首先检测三阴性乳腺癌中CD44-/CD24-细胞的肿瘤特性，其次比较初次纯化和去分化获得的BCSCs的干细胞特性差异，再次分析临床样本分离的原代细胞中FSIP1表达水平和CD44-/CD24-细胞去分化为BCSCs的相关性，最后探讨FSIP1是否通过Hippo/YAP/TAZ 通路调控CD44-/CD24-细胞去分化成BCSCs。本研究将初步阐明BCSCs特性维持机制，为三阴性乳腺癌的治疗提供新思路。

Breast cancer stem cells (BCSCs) are one of the main reasons leading to the metastasis of triple negative breast cancer(TNBC), and the regulation of the characteristics of BCSCs remains an open question. We reported that FSIP1 regulates the oncogenesis and invasiveness in breast cancer cells by binding to the intracellular domain of HER2 directly, may become a potential target for breast cancer therapy (PNAS, 2017). Our preliminary studies revealed that the purified CD44-/CD24- differentiated MDA-MB-231 dedifferentiated into CD44+/CD24- stem-like cells in vitro. The further purified CD44+/CD24- BCSCs had similar stemness compared to the primarily purified BCSCs. Furthermore, the knockout of FSIP1 by Crispr/Cas9 enhanced the dedifferentiation of CD44-/CD24- MDA-MB-231 cells into CD44+/CD24- BCSCs, followed by YAP/TAZ highly expression. Accordingly, we hypothesize that FSIP1-mediated microtubule disorders activate YAP/TAZ, together with stem cell related genes over expression, promote the dedifferentiation of triple negative breast cancer CD44-/CD24- into CD44+/CD24- BCSCs. We will examine the characteristics of triple negative breast cancer CD44-/CD24- cells and investigate the nature and mechanisms underlying the dedifferentiation of triple negative breast cancer CD44-/CD24- cells into CD44+/CD24- BCSCs. Theoretically, our findings may provide new insights into regulation of the stemness of BCSC and potentially aid in design of new therapies for triple negative breast cancers.