Atrap在AngII-AT1R介导的乳腺癌三苯氧胺耐药中的作用及机制

三苯氧胺耐药严重影响乳腺癌治疗效果，其机制仍未阐明。课题组既往研究证实：血管紧张素II/血管紧张素II受体1（AngII-AT1R）途径在乳腺癌肿瘤血管生成、凋亡及侵袭方面发挥作用(Cancer Letters 2013，J Cell Physiol 2014)。我们前期研究证实AngII-AT1R途径介导乳腺癌三苯氧胺耐药,并率先发现血管紧张素受体相关蛋白（Atrap）在人乳腺癌组织及三苯氧胺耐药细胞系高表达。已有文献证实Atrap是内吞转运的功能蛋白。我们推测Atrap调节AT1R内吞转运或直接与AT1R相互作用参与乳腺癌三苯氧胺耐药。我们将阐明Atrap在AT1R内吞转运中的作用并通过干预Atrap表达，观察乳腺癌三苯氧胺药物敏感性和AT1R表达及下游信号通路变化。本研究将揭示Atrap在AngII-AT1R介导的乳腺癌三苯氧胺耐药中的作用及机制，为克服乳腺癌三苯氧胺耐药提供靶点。

Tamoxifen resistance, as the primary cause to the failure of breast cancer endocrine therapy, its mechanism has not been elucidated. Our previous research has demonstrated that AngII-AT1R pathway plays an important role on tumor angiogenesis, apoptosis, invasion(Cancer Letters 2013，J Cell Physiol 2014).And subsequently we discovered that AngII-AT1R pathway mediate tamoxifen resistance in breast cancer(published). Most intriguingly, our latest results showed that Atrap, one angiotensin-associated protein, is highly expressed in both breast cancer tissue and tamoxifen resistant cell lines. Since it has been proved that Atrap is involved with endocytosis, we hypothesized that Atrap may modulate AT1R endocytosis or tamoxifen resistance in breast cancer by direct interaction with AT1R. Thus we are aiming to explore how Atrap regulates AT1R endocytosis and to investigate tamoxifen sensitivity in breast cancer and AT1R with its downstream signals change by interfering Atrap expression. The study may explore the role in which Atrap plays in AngII-AT1R mediated breast cancer tamoxifen resistance and provide a new target in overcoming tamoxifen resistance in breast cancer.