ARNO调控EGFR/HER3磷酸化介导乳腺癌Trastuzumab继发性耐药的作用机制研究

It is significant how to treat Trastuzumab resistance breast cancer well in clinc. One of the keys to solve the problem is finding the new molecular mechanisms. So we can find new therapeutic method for breast cancer further. Recent studies indicate that ARNO（cytohesin-2）is cytoplasmic ErbB receptor activators, which increase ErbB receptor autophosphorylation and activate lower mitogen pathway to stimulate tumor proliferation. We found that ARNO overexpression in acquired Trastuzumab resistance breast cancer cells(SkBr3/T), whereas underexpression in parental breast cancer cells (SkBr3). The increaseing EGFR, HER3 receptor autophosphorylation also can be find in SkBr3/T. Inhibition of ARNO can prove the Trastuzumab resistance breast cancer cells (MDA-MB-231)proliferation and imgration. So We think that ARNO help EGFR, IGF-1R signaling pathway, thus affecting the cancer cells’reaction to Trastuzumab .It demonstrats that ARNO protein is closley related with the proliferation and imgration of Trastuzumab resistance cancer cells. There are maybe one reason of the mechanism of Trastuzumab resistance .This study intends to illustrate and improve the mechanism of Trastuzumab resistance, which effect to the Trastuzumab resistance breast cancer proliferation, invasion and other biological behavior. it would provide new ideas and theoretical basis to the a possible follow-up of diagnosis and treatment method of breast cancer.

HER2阳性乳腺癌的曲妥珠单抗(Trastuzumab)耐药是临床面临的重要问题，解析原因，发现新的分子事件，是解决问题的方法之一。 最近发现调控蛋白ARNO是ErbB受体通路的重要参与者，其促进EGFR，HER3磷酸化，导致下游信号通路激活，促肿瘤增殖。我们发现Trastuzumab继发性耐药细胞系（SkBr3/T）相比Trastuzumab敏感的母系乳腺癌细胞系（SkBr3），出现了pEGFR，pHER3和ARNO上调；阻断ARNO能抑制Trastuzumab原发耐药乳腺癌细胞系MDA-MB-231（EGFR+HER2-）的增殖、迁移。故本研究拟在Trastuzumab继发性耐药细胞中探讨ARNO促进细胞增殖作用关键分子机制，明确其对EGFR，HER3为核心的代偿性活化信号通路的调控作用，为后续可能的临床诊治方案，提供新的思路和理论依据。

HER2阳性乳腺癌的曲妥珠单抗(Trastuzumab)耐药问题，是当前临床面临的重要问题，解析耐药原因，发现新的分子事件，为后续提出新诊治方案是解决问题的方法之一。 最近发现调控蛋白ARNO（Cytohesin-2）是ErbB受体通路的重要参与者，其促进ErbB受体(EGFR/HER3)磷酸化，导致下游丝裂原通路的激活，促进肿瘤增殖。本课题实验研究发现构建的Trastuzumab获得性耐药细胞系（SkBr3/T，BT474/T）较对Trastuzumab敏感的母系乳腺癌细胞系（SkBr3,BT474/T），出现了EGFR，HER3磷酸化上调，及ARNO的上调。我们体外实验证实肿瘤细胞在Trastuzumab治疗后，在ARNO协助下，促进ErbB受体家族部分亚型的活化，代偿活化下游增殖信号通路，促进肿瘤存活。故本研究证实了ARNO促进乳腺癌增殖产生Trastuzumab耐药存活，增殖的重要分子；明确了其对EGFR，HER3为核心的代偿性活化信号通路的调控作用；联合阻断ARNO与Trastuzumab联合对耐药的乳腺癌细胞系有协同抑制；为后续可能的临床诊治方案，提供新的思路和理论依据。