DDX11与FOXR2 相互作用在HER2 阳性乳腺癌曲妥珠单抗耐药的功能研究

耐药性是制约曲妥珠单抗抑癌效果的主要因素，而相关机制尚不甚清楚。本课题组前期工作表明：DDX11和FOXR2在曲妥珠单抗耐药HER2阳性乳腺癌细胞株中表达水平高于亲本对照组；它们相互结合并共定位于HER2阳性乳腺癌细胞核内；其过表达可增强HER2阳性乳腺癌细胞对曲妥珠单抗的耐药性。我们推测DDX11通过与FOXR2相互作用，启动关键性生存基因表达，进而诱导HER2阳性乳腺癌细胞获得曲妥珠单抗耐药性。为此，本课题拟：证实DX11与FOXR2诱导曲妥珠单抗耐药性的相互依赖性和协同作用；确定介导其相互作用的关键结构域；在全基因组范围内筛选FOXR2下游靶基因，鉴定介导DDX11和FOXR2促曲妥珠单抗耐药的关键效应基因；最后，在体内验证双靶向抑制DDX11和FOXR2对曲妥珠单抗耐药性的逆转作用。本研究将首次揭示DDX11与FOXR2相互作用对HER2阳性乳腺癌细胞对曲妥珠单抗耐药性的影响机制。

Drug resistance is the main factor restricting the anti-cancer effect of trastuzumab, and the mechanism is not yet clear. Our previous work showed that DDX11 and FOXR2 were higher expressed in trastuzumab-resistant HER2-positive breast cancer cell lines than in the parental control group; they were co-localized in cell nucleus of HER2-positive breast cancer cells and their overexpression can enhance the resistance to trastuzumab of HER2-positive breast cancer cells. We hypothesize that DDX11 initiates the expression of key survival genes by interacting with FOXR2, thereby inducing the trastuzumab resistance of HER2 positive breast cancer cells. To this end, the subject proposed: to confirmed the interdependence and interactions of DX11 and FOXR2 in the process of inducing the drug resistance to trastuzumab; to determine the key domains that mediate their interaction; to screen the FOXR2 downstream target genes at a whole-genome scale; to identify key effector genes that mediate the induction of trastuzumab resistance by DDX11 and FOXR2; and finally, to explore the reverse effects of DDX11’s and FOXR2’s double targeted inhibition regarding the trastuzumab resistance. This study will, for the first time, reveal the interactions between DDX11 and FOXR2 and their influence on the trastuzumab resistance of HER2 positive breast cancer cells.