Proteomic study reveals that proteins involved in metabolic and detoxification pathways are highly expressed in HER-2/neu-positive breast cancer
Proteomic study reveals that proteins involved in metabolic and detoxification pathways are highly expressed in HER-2/neu-positive breast cancer
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DOI：
10.1074/mcp.m400221-mcp200
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发表时间：
2005-11-01
影响因子：
7
通讯作者：
Koay, ESC
中科院分区：
文献类型：
--
作者：
Zhang, DH;Tai, LK;Koay, ESC
受体酪氨酸激酶ErbB 2（HER-2/neu）在高达30%的乳腺癌中过表达，与预后不良和转移可能性增加相关，特别是在淋巴结阳性肿瘤中。在该蛋白质组学研究中，为了鉴定与HER-2/neu阳性乳腺癌的侵袭性表型相关的蛋白质，通过激光捕获显微切割获得来自HER-2/neu阳性和阴性肿瘤的肿瘤细胞。通过二维电泳和MALDI-TOF/TOF MS/MS鉴定了两个肿瘤亚群中差异表达的蛋白质。我们发现了几个关键细胞周期调节剂的差异表达，这些调节剂与HER-2/neu过表达细胞的增殖增加有关。参与糖酵解的九种蛋白质（磷酸丙糖异构酶（TPI）、磷酸甘油酸激酶1（PGK 1）和烯醇化酶1（ENO 1））、脂质合成（脂肪酸合酶（FATIGUE）），应激介导的伴侣蛋白（热休克蛋白27（Hsp 27）），以及抗氧化和解毒途径（触珠蛋白、醛酮还原酶（AKR）、谷胱甘肽酶I（GLO）和脯氨酰-4-水解酶β-同种型（P4 HB））在HER-2/neu阳性乳腺肿瘤中被发现上调。通过免疫印迹法在4种乳腺癌细胞系和12种乳腺肿瘤中进一步验证PGK 1、FXR、Hsp 27和GLO的HER-2/neu依赖性差异表达，并通过赫赛汀治疗部分关闭HER-2/neu高表达SKBr 3细胞系中的HER-2/neu信号传导来证实。这些蛋白表达与HER-2/neu状态的统计学相关性通过免疫组织化学在包含97个乳腺肿瘤的组织微阵列上进一步验证。我们的研究结果表明，HER-2/neu信号传导可能直接或间接导致乳腺肿瘤微环境中各种代谢、应激反应、抗氧化和解毒过程的增强活化。我们假设，这些确定的细胞蛋白质组的变化很可能会驱动细胞增殖和组织侵袭，以及涉及的关键细胞周期调节剂，当未来的研究发现，将作为自然有用的目标，为发展的治疗策略，以否定HER-2/neu阳性乳腺肿瘤的转移潜力。
The receptor tyrosine kinase ErbB2 (HER-2/neu) is over-expressed in up to 30% of breast cancers and is associated with poor prognosis and an increased likelihood of metastasis especially in node-positive tumors. In this proteomic study, to identify the proteins that are associated with the aggressive phenotype of HER-2/neu-positive breast cancer, tumor cells from both HER-2/neu-positive and -negative tumors were procured by laser capture microdissection. Differentially expressed proteins in the two subsets of tumors were identified by two-dimensional electrophoresis and MALDI-TOF/TOF MS/MS. We found differential expression of several key cell cycle modulators, which were linked with increased proliferation of the HER-2/neu-overexpressing cells. Nine proteins involved in glycolysis (triose-phosphate isomerase (TPI), phosphoglycerate kinase 1 (PGK1), and enolase 1 (ENO1)), lipid synthesis (fatty acid synthase (FASN)), stress-mediated chaperonage (heat shock protein 27 (Hsp27)), and antioxidant and detoxification pathways (haptoglobin, aldo-keto reductase (AKR), glyoxalase I (GLO), and prolyl-4-hydrolase beta-isoform (P4HB)) were found to be up-regulated in HER-2/neu-positive breast tumors. HER-2/neu-dependent differential expression of PGK1, FASN, Hsp27, and GLO was further validated in four breast cancer cell lines and 12 breast tumors by immunoblotting and confirmed by partially switching off the HER-2/neu signaling in the high HER-2/neu-expressing SKBr3 cell line with Herceptin treatment. Statistical correlations of these protein expressions with HER-2/neu status were further verified by immunohistochemistry on a tissue microarray comprising 97 breast tumors. Our findings suggest that HER-2/neu signaling may result, directly or indirectly, in enhanced activation of various metabolic, stress- responsive, anti-oxidative, and detoxification processes within the breast tumor microenvironment. We hypothesize that these identified changes in the cellular proteome are likely to drive cell proliferation and tissue invasion and that the key cell cycle modulators involved, when uncovered by future research, would serve as naturally useful targets for the development of therapeutic strategies to negate the metastatic potential of HER-2/neu-positive breast tumors.