erbB2/HER2在肺癌组织中的表达及意义

目的：研究erbB2基因在肺癌的表达,方法：应用免疫组织化学的方法检测20例正常肺组织和60例肺癌HER2（第二人体表皮生长因子受体,human epidermal-growth-factor receptor2,HER2)蛋白的表达。结果：HER2在正常肺组织无过度表达,肺癌中存在HER2的过度表达,过度表达率为66.7%。肺癌HER2的过度表达更多见于中晚期的肺癌,且与患者术后3年生存率呈负相关。结论：HER2在正常肺组织无过度表达,在肺癌中存在过度表达,提示erbB2基因编码的HER2蛋白在细胞的正常生长及肺癌的发展中均起一定的作用。有可能成为观察肺癌预后的一个指标。     

erbB-4/HER4在膀胱癌中的表达研究

目的 检测第四人体表皮生长因子受体(human epidermal-growth-factor receptor 4,HER4)在膀胱癌组织中的表达,探讨HER4过度表达与膀胱癌临床病理的关系.方法 采用免疫组化方法检测71例膀胱癌组织中HER4的表达.结果 膀胱癌组织中HER4的过度表达率为77.5％.膀胱癌中HER4的过度表达仅与膀胱癌的生长方式及TNM分期相关.结论 erbB-4基因是膀胱癌生长的一个调控基因,干预HER4蛋白的过度表达可能是治疗膀胱癌的一种有效方法.     

非小细胞肺癌组织中FHIT和HER2的表达及其临床意义的研究

目的:探讨FHIT和HER2在非小细胞肺癌(non-small cell lung cancer,NSCLC)组织中的表达,及两者的联合表达对判断NSCLC预后和转归的价值。方法:SP法检测90例NSCLC标本中FHIT和HER2的表达。结果:NSCLC组织中FHIT蛋白失表达率53.75%(43/80)显著低于肺良性病变组织的10%(1/10),其失表达率与吸烟(P=0.000)、组织学类型(P=0.004)、淋巴结转移(P=0.002)、pTNM分期(P=0.028)及3年无瘤生存率(P=0.047)存在相关性。HER2蛋白的过表达率62.50%(50/80)却显著高于肺良性病变组织的0(0/10),其过表达率则与淋巴结转移与否(P=0.030)、pTNM分期(P=0.018)及3年无瘤生存率(P=0.028)存在相关性。FHIT蛋白的失表达与HER2蛋白过度表达呈显著负相关,P<0.05。结论:FHIT基因蛋白的失表达和HER2基因蛋白的过表达可能在NSCLC发生和发展过程中起重要作用,并影响预后。     

erbB4/HER4在非小细胞肺癌中的表达研究

目的：检测第四人体表皮生长因子受体（human epidermal-growth-factor receptor4,HER4)在非小细胞肺癌（non-small cell lung cancer,NSCLC)组织中的表达，探讨HER4过度表达与NSCLC临床病理特征之间的关系。方法：采用免疫组化法检测70例NSCLC（鳞癌43例，腺癌27例）和远离癌灶的20例正常组织中HER4的表达，结果：NSCLC中HER4过度表达率为91．4％（64／70）。HER4过度表达与NSCLC淋巴结转移（P＝0．007）、TNM分期（P＝0．011）及术后生存率（P＝0．0258）有密切关系。结论：er4bB4是晚期NSCLC生长的一个调控基因，干预HER4的过度表达可能是治疗晚期NSCLC的有效方法。     

IGF-1R、EGFR、VEGF、HER2在胃癌组织中的表达及与其预后的关系

目的探讨胰岛素样生长因子受体-1(IGF-1R)、表皮生长因子受体(EGFR)、血管内皮生长因子(VEGF)、人表皮生长因子受体2(HER2)在胃癌组织中表达及与胃癌预后的关系。方法采用免疫组化方法,检测108例胃癌组织中IGF-1R、EGFR、VEGF、HER2的表达水平,并结合其临床特点对其预后进行多因素综合分析。结果 108例胃癌组织中IGF-1R阳性表达67例(62%),EGFR阳性表达55例(51%),VEGF阳性表达46例(44%),HER2阳性表达22例(20%)。胃癌组织中IGF-1R与EGFR、VEGF、HER2表达两两呈正相关性,其中IGF-1R与HER2的相关性最强。影响胃癌患者预后多因素分析结果:IGF-1R、PTNM分期及Borrmann分型为胃癌预后独立因素,按其影响程度排序为:PTNM(HR 2.185,95%CI 1.623～2.941;P<0.001),IGF-1R(HR 1.755,95%CI 0.667～4.620;P=0.0255),Borrmann型胃癌(HR 1.174,95%CI 0.684～2.013;P=0.0261)。结论胃癌组织中IGF-1R阳性表达率最高;IGF-1R表达与EGFR、VEGF、HER2表达两两间呈正相关性,提示其在胃癌发生发展过程中存在协同作用;IGF-1R表达、PTNM分期及Borrmann分型对胃癌预后具有独立预测意义。     

乳腺癌HER2 过度表达预后相关因素研究

 目的　研究乳腺癌患者HER2 过度表达与其他临床预后因素的相关性及对预后的影响。方法 　收集我院2002 年1 月～2003 年12 月乳腺癌Ⅰ～ Ⅲ期患者共176 例,检测HER2 表达,与其他临床预 后因素进行相关分析;同时比较HER2 过度表达和阴性表达患者的预后。结果　本组患者HER2 过度 表达与PR( P = 0. 002) 、ER( P = 0. 031) 表达呈负相关,而与其他预后因素无相关性。多因素分析表明 HER2 是无病生存时间的独立预后因素( P = 0. 018) 。结论　HER2 过度表达可作为乳腺癌无病生存时 间的独立预后因素并指导乳腺癌的治疗。     

HER2在非小细胞肺癌临床分期中的预测价值

目的:人类表皮生长因子受体2(HER2)可能在肺癌的发生发展中,尤其在表皮生长因子受体1（EGFR）突变状态下,起着重要作用。我们探讨初治晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）血清HER2表达特征及临床意义。方法:本院肺癌研究所2012年9月到2013年6月血清标本共63例。用酶联免疫吸附测定法（ELISA）检测其外周血清中HER2表达水平。结果:HER2中位浓度为25.78ng/ml（10.29~488.28ng/ml）,HER2浓度在不同的肿瘤大小、淋巴结转移及远处转移均有显著性差异（P=0.007、P=0.024、P=0.046）。与淋巴结转移、远处转移呈负相关（P=0.012,P=0.005）。HER2血清浓度定量与年龄、性别、组织学分类、病理学类型、治疗前CEA浓度、吸烟状态、EGFR突变状态均无统计学意义。结论:在外周血清中检测HER2是可行的,与临床特征存在相关性,HER2在肺癌的发展过程中发挥重要作用。     

EGFR,HER2和HER3在胆管癌中的表达及预后价值

目的 观察表皮生长因子受体(Epidermal growth factor receptor,EGFR)、表皮生长因子受体2(Human epidermal growth factor receptor 2,HER2)和表皮生长因子受体3(Human epidermal growth factor receptor 3,HER3)在胆管癌(Cholangiocarcinoma,CCA)组织中的表达情况,探讨其与CCA患者临床病理特征、总生存期和CCA细胞增殖的关系。方法 收集2009年1月—2013年10月于我院手术的CCA患者50例,并同时收取癌旁组织作为对照。采用免疫组织化学方法及RT-PCR方法检测CCA及癌旁组织中EGFR、HER2和HER3表达情况。收集患者临床病理参数,分析EGFR、HER2和HER3表达与CCA临床病理参数之间的关系。绘制Kaplan-Meier生存曲线,采用Log-rank检验和Cox比例风险模型分析EGFR、HER2和HER3表达情况与50例CCA患者术后总生存期之间的关系。采用RNA干扰方法敲低CCA细胞株QBC939中EGFR、HER2和HER3表达,Western blot检测EGFR、HER2和HER3敲低效果,MTT方法检测EGFR、HER2和HER3对QBC939细胞增殖的影响。结果 CCA组织中可检测到EGFR、HER2和HER3的阳性表达。临床病理特征关系分析结果显示,HER2表达与CCA淋巴结转移相关(P＜0.05);而EGFR和HER3除与CCA淋巴结转移相关外,还与肿瘤分化程度相关(P＜0.05)。EGFR、HER2和HER3阳性患者术后总生存期明显低于阴性患者(P＜0.05)。敲低CCA QBC939细胞中EGFR、HER2和HER3表达后,QBC939细胞增殖能力显著降低(P＜0.05)。结论 CCA组织中EGFR、HER2和HER3表达与患者总生存期密切相关,机制可能与促进CCA细胞的增殖相关。     

乳腺癌患者HER2表达水平的不同检测方法比较及临床意义

目的 分析免疫组化法与荧光原位杂交技术(Fish)两种检测方法对乳腺癌患者人类表皮生长因子受体2(HER2)表达水平的检测价值.方法 选择248例乳腺癌患者,分别使用免疫组化法和Fish法检测乳腺癌组织中HER2的表达情况,随访3年,采用生存曲线分析HER2阳性乳腺癌患者的术后复发率.结果108例(43.55%)患者的免疫组化结果为HER2(-),54例(21.77%)患者为HER2(+),43例(17.34%)患者为HER2(++), 43例(17.34%)患者为HER2(+++).81例(32.66%)患者的Fish检测结果为阳性,167例(67.34%)患者为阴性.免疫组化法和Fish法对乳腺癌患者HER2检测结果的一致性较好,Kappa=0.937,P=0.000.生存曲线显示Fish阳性的乳腺癌患者术后复发率明显高于Fish阴性的乳腺癌患者(P=0.000),免疫组化HER2阳性的乳腺癌患者术后复发率明显高于HER2阴性的乳腺癌患者(P=0.000).结论 免疫组化法和Fish法对乳腺癌患者HER2检测结果的一致性较好,均可较好地反映患者预后.     

HER2与CD163在胃癌中的表达及意义

目的 研究人表皮生长因子受体-2(human epidermal growth factor receptor-2,HER2)与M2型巨噬细胞表面标志物分化抗原簇163(cluster of differentiation 163,CD163)在胃癌组织中的表达及意义.方法 应用免疫组织化学方法检测45例胃癌和癌旁组织标本中HER2、CD163和CD68蛋白的表达,并将检测结果与患者临床病理资料相结合进行综合分析.结果 胃癌组织中的CD163+和CD68+细胞数目高于癌旁组织(均P＜0.05),HER2阳性表达在肿瘤pTNM分期、有无淋巴结转移等方面差异有统计学意义(均P＜0.05).CD163+ M2巨噬细胞数在肿瘤pTNM分期方面差异有统计学意义(P＜0.05).HER2蛋白表达与CD163+ M2性巨噬细胞数目存在相关性(r=0.61,P＜0.05).结论 HER2表达强度与M2型巨噬细胞数目存在相关性,二者是判断胃癌诊断、治疗及预后的重要参考指标.     

HER2和BRCA1在子宫内膜癌中的表达及其与预后的关系

目的探讨人表皮生长因子受体-2(human epidermal growth factor receptor 2,HER2)和乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)在子宫内膜癌中的表达及其与预后的关系。方法采用免疫组织化学方法检测79例子宫内膜癌、40例非典型增生子宫内膜、30例正常子宫内膜组织中HER2与BRCA1的表达,并结合随访资料分析这2个指标与患者生存时间的关系。结果在正常子宫内膜、非典型增生子宫内膜、子宫内膜癌中HER2阳性表达率分别为6.7%、17.5%、67.1%(P=0.000),BRCA1阳性表达率分别为93.3%、62.5%、31.7%(P=0.000)。子宫内膜癌中,HER2阳性表达与组织分化、手术病理分期、肌层浸润及淋巴结转移有关(均P<0.05),BRCA1阳性表达与组织分化、手术病理分期及淋巴结转移有关(均P<0.05);HER2阳性表达患者的5年生存率低于HER2阴性表达患者(69.8%vs 92.3%,P<0.05),BRCA1阳性表达患者与阴性表达患者的5年生存率差异无统计学意义(84.6%vs 72.2%,P>0.05);BRCA1与HER2蛋白在子宫内膜癌中表达无相关性(r=-0.103,P>0.05)。结论 BRCA1的表达缺失可能与子宫内膜癌的发生、发展有关,HER2蛋白的高表达与子宫内膜癌侵袭性及不良预后有关。     

Expression of PAM50 Genes in Lung Cancer: Evidence that Interactions between Hormone Receptors and HER2/HER3 Contribute to Poor Outcome

Non–small cell lung cancers (NSCLCs) frequently express estrogen receptor (ER) β, and estrogen signaling is active in many lung tumors. We investigated the ability of genes contained in the prediction analysis of microarray 50 (PAM50) breast cancer risk predictor gene signature to provide prognostic information in NSCLC. Supervised principal component analysis of mRNA expression data was used to evaluate the ability of the PAM50 panel to provide prognostic information in a stage I NSCLC cohort, in an all-stage NSCLC cohort, and in The Cancer Genome Atlas data. Immunohistochemistry was used to determine status of ERβ and other proteins in lung tumor tissue. Associations with prognosis were observed in the stage I cohort. Cross-validation identified seven genes that, when analyzed together, consistently showed survival associations. In pathway analysis, the seven-gene panel described one network containing the ER and progesterone receptor, as well as human epidermal growth factor receptor (HER)2/HER3 and neuregulin-1. NSCLC cases also showed a significant association between ERβ and HER2 protein expression. Cases positive for HER2 expression were more likely to express HER3, and ERβ-positive cases were less likely to be both HER2 and HER3 negative. Prognostic ability of genes in the PAM50 panel was verified in an ERβ-positive cohort representing all NSCLC stages. In The Cancer Genome Atlas data sets, the PAM50 gene set was prognostic in both adenocarcinoma and squamous cell carcinoma, whereas the seven-gene panel was prognostic only in squamous cell carcinoma. Genes in the PAM50 panel, including those linking ER and HER2, identify lung cancer patients at risk for poor outcome, especially among ERβ-positive cases and squamous cell carcinoma.Abbreviations: NSCLC, non–small cell lung cancer, ER, estrogen receptor, PGR, progesterone receptor, HR, hazard ratio, HER2, human epidermal growth factor receptor 2, HER3, human epidermal growth factor receptor 3, FFPE, formalin-fixed, paraffin embedded, PCA, principal component analysis, DFS, disease-free survival, PFS, progression-free survival, OS, overall survival, TCGA, The Cancer Genome Atlas, PAM50, prediction analysis of microarray 50 gene set, IHC, immunohistochemistry, IPA, Ingenuity Pathway Analysis     

Expression of HER2 and its association with AP-2 in breast cancer

The aim of the study was to investigate the relationship between the expression of human epidermal growth factor receptor 2 (HER2) and activator protein 2 (AP-2), as well as the prognostic significance of HER2 in breast cancer. HER2 and AP-2 expressions were immunohistochemically (IHC) analysed in a large prospective, consecutive series of 425 breast cancer patients diagnosed and treated between 1990 and 1995 at the Kuopio University Hospital, Kuopio, Finland. In a subset of patients (n = 71), the gene amplification status was examined by using a chromogenic in situ hybridisation (CISH) analysis. Expression of HER2 was studied in relation to AP-2, clinicopathological parameters and patients' survival. Pathological membranous overexpression of the HER2 receptor was seen in 13% of the carcinomas, which was related both to gene amplification (78% of the cases) and high nuclear expression of AP-2 (67%, P = 0.007). HER2-positivity was most often seen in carcinomas having both high nuclear and high cytoplasmic AP-2 expression (P < 0.001). In the univariate survival analyses HER2-positivity predicted a shorter recurrence-free survival (RFS) (P < 0.0001) and a shorter breast cancer-related survival (BCRS) (P = 0.0063) in the whole patient group, as well as in the subgroup of node-negative patients. In the node-positive patients, HER2-positivity predicted only a shorter RFS. Combined expression of HER2 and nuclear AP-2 resulted in the separation of four groups with different prognoses, the best prognosis being for patients in the HER2-/AP-2+ group and the worse prognosis for those in the HER2+/AP-2- group. In the multivariate survival analyses, HER2-positivity independently predicted a shorter RFS in the whole patient group (P = 0.0067), as well as in the subgroup of node-positive patients (P = 0.0209). In conclusion, pathological membranous overexpression of the HER2 receptor in breast cancer is related both to gene amplification and a high AP-2 expression. Combining HER2 and AP-2 expressions may provide valuable information on the prognosis of breast cancer patients.     

MUC1与HER2基因在乳腺癌中的表达及其与临床病理学指标的相关性研究

目的：检测粘蛋白1（mucinl，MUC1）和人类表皮生长因子2（Human epidermal growth factor receptor 2，HER2）在乳腺癌组织中的表达，研究其与临床、病理学因子的关系及MUC1与HER2的相关性。方法：应用免疫组化SP法检测111例乳腺癌组织，37例良性乳腺肿瘤和26例癌旁正常组织中MUC1和HER2的表达情况。结果：MUC1和HER2在乳腺癌中的表达率分别为83．78％、46．85％，与良性肿瘤及癌旁正常组织比较，均有显著性差异。乳腺癌组织中，MUC1表达与腋窝淋巴结转移、临床TNM分期有关，与年龄、肿瘤大小、组织学分级、病理类型无关。HER2表达与组织学分级、临床TNM分期有关，与年龄、肿瘤大小、淋巴结转移、病理类型无关。MUC1与HER2表达呈显著正相关，r=0．197，P=0．038。结论：MUC1与HER2基因的联合监测对判断乳腺癌的恶性程度，淋巴转移，预后及治疗有重要意义．     

Expression of HER2 and estrogen receptor alpha depends upon nuclear localization of Y-box binding protein-1 in human breast cancers

In our present study, we examined whether nuclear localization of Y-box binding protein-1 (YB-1) is associated with the expression of epidermal growth factor receptors (EGFR), hormone receptors, and other molecules affecting breast cancer prognosis. The expression of nuclear YB-1, clinicopathologic findings, and molecular markers [EGFR, HER2, estrogen receptor (ER)alpha, ER beta, progesterone receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), phosphorylated Akt, and major vault protein/lung resistance protein] were immunohistochemically analyzed. The association of the expression of nuclear YB-1 and the molecular markers was examined in breast cancer cell lines using microarrays, quantitative real-time PCR, and Western blot analyses. Knockdown of YB-1 with siRNA significantly reduced EGFR, HER2, and ER alpha expression in ER alpha-positive, but not ER alpha-negative, breast cancer cell lines. Nuclear YB-1 expression was positively correlated with HER2 (P = 0.0153) and negatively correlated with ER alpha (P = 0.0122) and CXCR4 (P = 0.0166) in human breast cancer clinical specimens but was not correlated with EGFR expression. Nuclear YB-1 expression was an independent prognostic factor for overall (P = 0.0139) and progression-free (P = 0.0280) survival. In conclusion, nuclear YB-1 expression might be essential for the acquisition of malignant characteristics via HER2-Akt-dependent pathways in breast cancer patients. The nuclear localization of YB-1 could be an important therapeutic target against not only multidrug resistance but also tumor growth dependent on HER2 and ER alpha.     

The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients

Increased expression of the epidermal growth factor (EGF) receptors, HER1 and HER2 are related to poor prognosis in most cancers studied. Recently, a high expression of the two remaining receptors of the EGF system, HER3 and HER4 has been related to a favourable prognosis. However, prognostic significance of HER1 and HER2 receptors in bladder cancer is controversial and the effect of the expression of different combinations of these receptors on patient survival is not well understood. Therefore, we examined the mRNA expression of all four EGF receptors with real-time polymerase chain reaction in biopsies from 88 patients with bladder cancer, where the survival was followed for a median of 38.5 months (range 1-117 months). Expression of HER1 and HER2 alone showed no correlation with survival. However, a high expression of HER1 together with high expression of HER3 and HER4 correlated to a better prognosis compared to the high expression of HER1 together with low expression of HER3 and HER4 (P=0.0006). Also, a significantly longer survival was observed in patients expressing high HER2 when coexpressed with high HER3 and HER4, as compared to the survival in patients with tumours expressing high HER2 but low HER3 and HER4 (P=0.0005). Our results suggest that the final outcome of patients with high HER1- and HER2-expressing tumours depends on the expression of HER3 and HER4.     

Targeting HER1/EGFR in cancer therapy: experience with erlotinib

Research into the role of the human epidermal receptor growth factor receptor 1/epidermal growth factor receptor (HER1/EGFR) in tumorigenesis has generated a new class of anticancer drugs. One such agent, erlotinib (Tarceva), is a potent, selective and reversible inhibitor of HER1/EGFR tyrosine kinase activity. Erlotinib has demonstrated the clinical activity in a variety of solid tumors, and has recently demonstrated improvements in survival in large Phase III trials, in non-small-cell lung cancer and pancreatic cancer.     

Evaluation of HER2-based biology in 1,006 cases of gastric cancer in a Japanese population

Background

The ToGA trial demonstrated the beneficial effect of trastuzumab in gastric cancer patients with human epidermal growth factor receptor 2 (HER2)-overexpressing tumors. Therefore, evaluation of the relationship between HER2 expression and gastric cancer biology using a validated system has become an even more important task. Herein, we verified the correlation between HER2 overexpression in the tumor and the clinical course of gastric cancer patients.

Methods

A total of 1,006 consecutive patients with gastric cancer who underwent surgery at the National Cancer Center Hospital East between January 2003 and July 2007 were examined using the tissue microarrays approach. HER2 expression was determined based on an immunohistochemistry score of 3+, or an immunohistochemistry score of 2+ plus HER2 gene amplification as detected by double-color fluorescent in situ hybridization. A retrospective review of the medical records was conducted to determine the correlation between the presence of HER2 overexpression and clinicopathological factors. Then, in 948 patients who had undergone curative resection, HER2 status was compared with the survival.

Results

HER2 overexpression was detected in 118 (11.7 %) patients. HER2 overexpression was correlated with age, gender, grade of differentiation, expanding growth pattern, and nodal status. In the survival analysis, HER2 overexpression was not found to be correlated with either disease-specific survival or recurrence-free survival.

Conclusions

HER2 overexpression in the tumor was not identified as a significant prognostic factor in patients with operable gastric cancer. The HER2-targeted therapy may be beneficial in a proportion of cases.