Ebp1与Anxa2相互作用促进乳腺癌细胞他莫昔芬耐药的分子机制研究

他莫昔芬（TAM）耐药是激素受体阳性乳腺癌治疗失败的重要原因，具体机制尚不明确。目前研究表明EGFR信号通路激活是导致TAM耐药的主要原因，近年来有报道上皮间质转化（EMT）和TAM耐药具有相关性。我们前期研究发现，Anxa2通过EGFR信号通路介导激素受体阳性乳腺癌细胞的EMT；随后的蛋白组学发现Ebp1是Anxa2相互作用网络的核心蛋白，其表达影响Anxa2的激活，而Ebp1也是EGFR家族成员的结合蛋白并调控细胞对TAM的敏感性。因此我们推测：Ebp1通过与Anxa2相互作用介导EGFR信号通路的激活从而调控TAM耐药。本研究将通过一系列分子和细胞生物学实验及动物模型，阐明Ebp1对Anxa2的调控模式，明确Anxa2和Ebp1的表达变化对激素受体阳性乳腺癌细胞EMT、TAM敏感性以及EGFR信号通路活化的影响。其研究成果将丰富TAM耐药的机理，为耐药乳腺癌治疗提供新的靶点和思路。

Tamoxifen is the most commonly used agent in endocrine therapy of breast cancer. TAM resistance is the main cause of treatment failure in hormone receptor positive breast cancer, however, the accurate mechanism remains unclear. Activation of EGFR signaling pathway has been regarded as the leading cause of TAM resistance; recently, it has been reported that epithelial-mesenchymal transition (EMT) was involved in TAM resistance. We previously showed that Anxa2 is the key factor to mediate EMT of hormone receptor-positive breast cancer cells through the EGFR signaling pathway. The proteomic results showed that Ebp1 is the core protein of the Anxa2-interacting network, which also affects the activation of Anxa2. In addition, Ebp1 is also a binding protein of EGFR family members and was reported as a regulatory protein of TAM sensitivity. Therefore, we hypothesize that: Ebp1 interacts with Anxa2 and regulates TAM resistance in hormone receptor positive breast cancer cell through the mediation of activation of EGFR signaling pathway. In this study, we plan to employ a series of molecular biology, cell biology experiments and in vivo SCID animal models to elucidate the details of how Epb1 interacts with Anxa2, and to investigate the potential effect of Ebp1 and Anxa2 knockdown on EMT, TAM sensitivity, and activation of EGFR signaling pathway in hormone receptor positive breast cancer cells. Our study will provide new knowledge to better understand the molecular mechanism of TAM resistance, and provide clues for finding new molecular targets for the treatment of patients with TAM resistance.