关键词：乳腺癌;染色质;临床研究;克隆;控制;果蝇;基因;基因;体内分析;抑制;杀伤力;转移;模型;调节器;突变;肿瘤;预防;预防医学;等级次序统计;耐药性;感觉器官;表面;目标;转换
摘 要：We combine fly genetics with haploid ES cell mutagenesis and in vivo mouse genetics to functionally characterize human candidate breast cancer genes. Using mouse genetics we have progressed in defining the role of RANKL/RANK in breast cancer. Moreover, we have first results that deletion of RANK might affect the development of BRCA1-mutant breast cancer. If correct this might lead to first cancer prevention trials in BRCA1 carriers using RANKL blockade. Using Drosophila modeling of Ras-driven transformation, we performed a near-genome wide screen for genes that control tumor progression. Using this system we have functionally identified multiple novel cancer genes that also play a role in breast cancer, e.g. the surface receptor TSPAN6 or the chromatin modulator EPC1. Finally, we have progressed in generating a haploid ES cell library for all researchers and have already generated more than 27000 murine ES cell clones targeting more than 10000 different genes. These integrations are repairable and each clone carries a genetic barcode, essential to perform future synthetic lethal experiments or to uncover resistance to defined drugs. Thus, we have successfully initiated all proposed aims with the vision to provide rapid functional annotation of breast cancer genes and, in case or RANKL/RANK, to provide the essential rationale for clinical prevention trials.