Tid1, CHIP and ErbB2 interactions and their prognostic implications for breast cancer patients
Tid1, CHIP and ErbB2 interactions and their prognostic implications for breast cancer patients
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DOI：
10.1002/path.2921
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发表时间：
2011-11-01
影响因子：
7.3
通讯作者：
Lo, Jeng-Fan
中科院分区：
文献类型：
--
作者：
Jan, Chia-Ing;Yu, Cheng-Chia;Lo, Jeng-Fan
ErbB2 （HER2/neu）在约25-30%的乳腺恶性肿瘤中过表达，乳腺癌患者中ErbB2上调与预后不良相关。已知热休克同源70相互作用蛋白（CHIP）的羧基端在体外有效下调ErbB2。人肿瘤影像盘1 （Tid1, DnaJa3）是热休克蛋白70 （Hsp70）的共同伴侣，在乳腺癌细胞系中也抑制ErbB2的表达。然而，Tid1、CHIP和ErbB2之间的细胞内相互作用仍然难以捉摸，并且从未提出将Tid1和CHIP用作乳腺癌生物标志物。本文采用免疫组织化学（IHC）和免疫印迹法分析了Tid1、CHIP和ErbB2在183例乳腺癌组织切片（包括30例新鲜组织标本）中的表达及其相关性。计算机图像分析系统用于免疫组化评分和确定相对免疫印迹强度。Tid1和CHIP的免疫组化表达与ErbB2呈负相关，两者呈正相关。优势比分析显示，Tid1的低表达相对较高的风险为不良肿瘤分级、较晚的病理分期、较大的肿瘤大小，以及更恶性的显微组织学特征，包括淋巴血管侵袭、间质炎症反应和肿瘤坏死。CHIP的表达也表现出类似的特征。此外，Tid1和/或CHIP的表达增加了患者的10年总生存率和无病生存率。通过免疫荧光或共免疫沉淀分析，我们也证实了Tid1、CHIP和ErbB2之间存在相互作用。功能上，Tid1和CHIP在体外协同降解ErbB2。相反，Tid1不能弥补CHIP突变中ErbB2降解所引起的蛋白水解功能的丧失。总的来说，我们的数据表明Tid1和CHIP在影响ErbB2蛋白水平方面起关键作用，两者都是乳腺癌患者生存的重要预后指标。版权。(C) 2011年英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
ErbB2 (HER2/neu) is overexpressed in about 25-30% of breast malignancies, and up-regulation of ErbB2 in breast cancer patients is associated with poor prognosis. It is known that the carboxyl terminus of heat shock cognate 70 interacting protein (CHIP) efficiently down-regulates ErbB2 in vitro. Human tumourous imaginal disc 1 (Tid1, DnaJa3), a co-chaperone of heat shock protein 70 (Hsp70), also suppresses ErbB2 expression in breast cancer cell lines. However, the intracellular interactions among Tid1, CHIP, and ErbB2 remain elusive, and the utilization of Tid1 and CHIP as breast cancer biomarkers has never been proposed. Herein, we analysed the expression and correlations among Tid1, CHIP, and ErbB2 in a total of 183 breast cancer histology sections, including 30 fresh tissue specimens, using immunohistochemistry (IHC) and immunoblotting assay. A computerized image analysis system was used for IHC scoring and determining relative immunoblot intensity. The immunohistochemical expression of Tid1 and CHIP were positively correlated with each other but were both inversely correlated to that of ErbB2. Odds ratio analyses showed that lower expression of Tid1 has a relatively higher risk of unfavourable tumour grade, later pathological stage, larger tumour size, and microscopic features of a more malignant histology including lymphovascular invasion, stromal inflammatory response, and tumour necrosis. Expression of CHIP displayed similar characteristics. Furthermore, expression of Tid1 and/or CHIP increases patients' 10-year overall and disease-free survival rate. Empirically, we also demonstrated that Tid1, CHIP, and ErbB2 interacted with each other through immunofluorescence or co-immunoprecipitation analyses. Functionally, Tid1 and CHIP acted synergistically to degrade ErbB2 in vitro. Conversely, Tid1 cannot compensate for the loss of proteolytic function noted in CHIP mutations for degradation of ErbB2. Overall, our data suggest that Tid1 and CHIP play pivotal roles in affecting the levels of ErbB2 protein, and that both are significant prognostic indicators of breast cancer patient survival. Copyright. (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.