三阴性与三阳性乳腺癌定量蛋白质组学和生物信息学比较研究

目的：雌／孕激素受体（estrogen receptor／progesterone receptor，ER／PR）和癌基因人表皮生长因子受体2（hu-man epidermal growth factorreceptor2，HER2）与乳腺癌的发生和发展密切相关，其表达状态是乳腺癌分子分型、治疗方案选择和预后预测的重要依据。为了深入探讨 ER／PR／HER2在乳腺癌发生和恶性演进中的意义及相关机制，拟建立ER／PR／HER-2阴性和阳性乳腺癌的蛋白质表达谱，寻找 ER／PR／HER-2阴性和阳性乳腺癌中差异表达蛋白，为乳腺癌患者提供新的预后预测指标和治疗新靶点。方法应用蛋白质组学同位素相对标记与绝对定量（isobaric tags for rela-tive and absolute quantitation，iTRAQ）技术建立 ER／PR／HER-2阳性和阴性乳腺癌的蛋白质差异表达谱，鉴定2组乳腺癌的差异表达蛋白，对部分差异表达蛋白进行生物信息学分析，包括蛋白功能注释、基因本体论分类分析（gene ontology classification analysis，GO 分析）和京都基因与基因组百科全书（Kyoto encyclopedia of gene and genome，KEGG）通路分析。结果应用 iTRAQ 蛋白质组学技术对乳腺癌组织进行了蛋白组学分析，鉴定出 ER／PR／HER-2阳性和阴性组间有差异表达的蛋白4999种，以 ER／PR／HER-2阳性∶ER／PR／HER-2阴性≥3为上调标准，确定 ER／PR 阳性组上调蛋白73种。以 ER／PR／HER-2阳性∶ER／PR／HER-2阴性≤0．5为下调标准，ER／PR／HER-2阳性组下调蛋白58种。GO 分析结果显示，ER／PR／HER-2阴性和阳性乳腺癌差异表达蛋白的分子功能、生物过程和细胞定位较为复杂，并且在上调蛋白和下调蛋白上存在分布差异。KEGG 通路分析发现，部分差异表达蛋白涉及200条信号通路。结论 ER／PR／HER-2阳性和阴性乳腺癌间存在差异表达蛋白，这些蛋白涉及复杂的分子功能、生物过程和信号通路，可能与 ER／PR／HER-2的表达状态有关。

Comparative quantitative proteomic and bioinformatics study of triple positive and triple negative breast cancer

OBJECTIVE Estrogen/progesterone receptor (PR)and oncogene HER-2 are closely related to breast cancer occurrence and development,its expression is an important basis for the prediction of breast cancer molecular classi-fication,treatment and prognosis.In order to further investigate the significance and related mechanism of the ER/PR/HER-2 in malignant progression of breast cancer,this study planed to establish differentially expressed proteins profiles for ER/PR/HER-2 negative and positive breast carcinoma,and provide new prognostic markers and therapeutic targets for patients with ER/PR/HER-2 positive breast cancer.METHODS By proteomic iTRAQ technology,ER/PR/HER-2 posi-tive and negative breast cancer protein expression profiles were established,differences of protein expression were identi-fied and parts of differential expression protein were analyzed by bioinformatics analysis,including protein function annota-tion and GO classification analysis and KEGG pathway analysis.RESULTS iTRAQ proteomic analysis of breast cancer tissue with identified ER/PR/HER-2 positive and negative groups showed 4 999 differentially expressed protein.While ratio of ER/PR/HER-2(+)/ER/PR/HER-2(-)was more than or equal to 3 for standard cut,73 up-regulated proteins in ER/PR/HER-2 positive group were identified.In ER/PR/HER-2(+)/ER/PR/HER-2(-)less than or equal 0.5 for standard cut,58 down-regulated proteins were identified in ER/PR/HER-2 positive group.The results of GO analysis showed that the cellular composition,molecular function,biological process of differentially expressed proteins were com-plex between ER/PR/HER-2 positive and negative breast cancer,and there were differences in the distribution of up-regu-lated proteins and down-regulation of proteins.KEGG pathway analysis showed that differentially expressed proteins in-volved in 200 signal pathways.CONCLUSION There are differentially expressed proteins between ER/PR/HER-2 posi-tive and negative breast cancer,which involves complex molecular function,biological process and signaling pathway, which may be related to the expression state of ER/PR/HER-2.