抗痛风药苯溴马隆通过EYA/Six1通路逆转三阴性乳腺癌多药耐药的作用及机制

Multidrug resistance is a major obstacle in cancer chemotherapy, which is responsible for refractory and recurrent of triple-negative breast cancers (TNBC). An increasing body of evidence suggests that survival of a small population of cells with stem-like properties may be responsible for these tumor recurrences after an initial response to chemotherapy. This population, called cancer stem-like cells (CSC), retains the capacity to self-renew and regenerate the total bulk of a heterogeneous tumor comprised mostly of non–stem cells. The CSC theory postulates that the stem cells are the cells that need to be killed to eradicate the tumor. However, there is still lack of effective targets and drugs for eliminating CSC to reverse multidrug resistance. Six1 signaling is the key pathway to drive breast tumorigenesis, including Six1 and EYA. Our previous studies and other researches suggest that Six1 could confer multidrug resistance through regulation self-renew of CSC, which is dependent on the phosphates activity of EYA for enhancement of cancer stem/progenitor cell characteristics. It also has been showed that the EYA tyrosine phosphatase activity could be inhibited by the anti-goat drug benzbromarone. We therefore hypothesize that benzbromarone may reverse multidrug resistance through inhibition of EYA/Six1 signaling. In this study, mechanistic and functional studies will be performed to confirm whether benzbromarone could reverse multidrug resistance in TNBC. A better understanding of the role of benzbromarone in the drug resistance may thus pave the way for novel and powerful anticancer therapeutics for reversing multidrug resistant in TNBC, and which is very important in both theoretical researches and clinical application.

三阴性乳腺癌（TNBC）是当前乳腺癌治疗的瓶颈，多药耐药的产生是其复发难治的主要原因。肿瘤干细胞（CSC）理论认为，CSC是肿瘤多药耐药产生的根源，只有针对性杀灭CSC才能逆转耐药。但是，目前仍缺乏针对CSC的逆转耐药的有效靶点和药物。Six1通路是驱动乳腺癌发生的关键通路，主要成员有Six1和EYA等。我们的前期研究和既往文献提示，Six1通过调控CSC的自我更新介导TNBC多药耐药，且该过程依赖于EYA的磷酸酶活性。此外，最近研究发现抗痛风药苯溴马隆可特异性抑制EYA的磷酸酶活性。因此我们推测：苯溴马隆可通过抑制EYA的磷酸酶活性，进而影响Six1促进CSC自我更新的能力，并最终逆转TNBC多药耐药。本课题将从细胞和整体水平系统研究苯溴马隆逆转TNBC多药耐药的作用，并对其分子机制进行深入探讨。本项目的实施有望为逆转TNBC多药耐药提供新的靶点和药物，具有重要的科学意义和临床应用价值。

三阴性乳腺癌（TNBC）是当前乳腺癌治疗的瓶颈，多药耐药的产生是其复发难治的主要原因。肿瘤干细胞（CSC）理论认为，CSC是肿瘤多药耐药产生的根源，只有针对性杀灭CSC才能逆转耐药。但是，目前仍缺乏针对CSC的逆转耐药的有效靶点和药物。Six1通路是驱动乳腺癌发生的关键通路，主要成员有Six1和EYA等。通过研究我们发现，Six1通过调控CSC的自我更新参与TNBC多药耐药，且该过程依赖于EYA的磷酸酶活性。苯溴马隆可通过抑制EYA的磷酸酶活性，进而影响Six1促进CSC自我更新的能力，并最终逆转TNBC多药耐药。本课题从细胞和整体水平系统研究苯溴马隆逆转TNBC多药耐药的作用，并对其分子机制进行深入探讨。本项目的实施为逆转TNBC多药耐药提供新的靶点和药物，具有重要的科学意义和临床价值。