トリプルネガティブ乳癌におけるプロテアソーム関連因子PAG1による新規増殖機構の解明

Triple negative breast cancer （TNBC） is considered to be one of the most aggressive subtypes of all breast cancers. To identify novel potential therapeutic targets and clarify pathophysiological features for TNBC, we conducted Meta-gene profiling analysis based on gene-expression profiling of TNBC cases purified by lasermicrobeam microdissection, and found that proteasome-associated genes （PAGs） were commonly upregulated in various pathways including cell cycle regulation in TNBC. Depletion of PAGs with RNAi caused the upregulation of p27 and p21 proteins in MDA-MB-231 and HCC1937 cells, respectively, resulting in growth inhibition. Interestingly, immunocytochmical staining revealed that PAG1 was observed in the nucleoli and/or cytoplasm （n-PAG1 and c-PAG1） in TNBC cell line and clinical specimens. Immunohistochemical staining of 100 TNBCs showed that high level of n-PAG1 was significantly associated with poor disease free and overall survival of TNBC patients. These results indicate that n-PAG1 plays a critical role in nucleus during cell cycle progression and might be a novel prognostic indicator or an attractive molecular target of TNBC.