HER2/neu在肿瘤中研究进展及抗HER2/neu治疗

HER2/neu是酪氨酸受体家族成员之一,主要通过Ras/MAPK、PI3K/Akt等通路参与细胞的增殖及抗凋亡,通过促进基质金属蛋白酶(MMPs)分泌、激活VEGF的启动子,同时激活丝氨酸/苏氨酸激酶(AKT)及核因子KB(NF-KB)等,促进肿瘤的浸润及转移。HER2/neu蛋白的过表达和基因扩增存在于多种肿瘤中,包括乳腺癌、肺癌、卵巢癌、消化道肿瘤等。关系到肿瘤的发生、发展、转移、治疗及预后。目前抗HER2/neu治疗药物大体可分为4类:作用于受体细胞外区域的抗体、小分子酪氨酸激酶抑制剂、抗体-细胞毒分子耦合剂和伴侣蛋白拮抗剂。现对其与肿瘤的研究现状及抗HER2/neu的治疗作一综述。     

HER2/neu在肿瘤中研究进展及抗HER2/neu治疗

HER2/neu是酪氨酸受体家族成员之一,主要通过Ras/MAPK、PI3K/Akt等通路参与细胞的增殖及抗凋亡,通过促进基质金属蛋白酶（MMPs）分泌、激活VEGF的启动子,同时激活丝氨酸/苏氨酸激酶（AKT）及核因子KB（NF-KB）等,促进肿瘤的浸润及转移。HER2/neu蛋白的过表达和基因扩增存在于多种肿瘤中,包括乳腺癌、肺癌、卵巢癌、消化道肿瘤等。关系到肿瘤的发生、发展、转移、治疗及预后。目前抗HER2/neu治疗药物大体可分为4类：作用于受体细胞外区域的抗体、小分子酪氨酸激酶抑制剂、抗体-细胞毒分子耦合剂和伴侣蛋白拮抗剂。现对其与肿瘤的研究现状及抗HER2/neu的治疗作一综述。     

HER2/neu受体酪氨酸激酶抑制剂SUCI02对乳腺癌细胞周期的影响及其分子机理

目的:探讨SUCI02对HER2受体过表达的乳腺癌细胞周期分布的影响及其分子机制.方法:采用免疫印迹法检测蛋白表达量和磷酸化蛋白量的变化;流式细胞术检测细胞周期的分布.RT-PCR检测mRNA的表达.结果:SUCI02处理MDA-MB-453细胞24h后,流式细胞仪分析可见在0、2.5、5、10、20μg/ml浓度下,MDA-MB-453细胞G0/G1期分别为:59.5%、65.8%、68.2%、70.0%、79.0%;S期分别为:38.1%、31.9%、29.4%、27.4%、18.3%;G2M期分别为:2.4%、2.3%、2.4%、2.6%、2.7%.不同浓度的SUCI02处理MDA-MB-453细胞24h后,细胞中p27上调,Rb的高磷酸化状态下降,Cvclin D1蛋白水平在10、20μg/ml SUCI02作用下显著下降.RT-PCR检测结果可见SUCI02对Cyclin D1的mRNA表达有明显的抑制作用.结论:SUCI02能诱导HER2/neu过表达的乳腺癌MDA-MB-453细胞停止于G1期,且与p27上调、Rb的高磷酸化状态下降、Cyclin D1 mRNA和蛋白水平下降有关.     

乳腺癌HER—2／neu基因检测与Herceptin治疗

研究发现ＨＥＲ 2 /ｎｅｕ基因扩增或过表达的乳腺癌倾向于早期复发且患者生存期缩短 ,且化疗及三苯氧胺治疗效果不佳 ,这种基因对乳腺癌患者极为不利。人们希望能有 1种抗癌基因的药物问世 ,特别是抗ＨＥＲ 2 /ｎｅｕ基因的药物 ,既具有下调ＨＥＲ 2 /ｎｅｕ基因的作用 ,又可增强对化疗药物的敏感性 ,延长患者的生命。近年Ｈｅｒｃｅｐｔｉｎ的研制成功给乳腺癌治疗带来了希望 ,开辟了生物学靶向治疗的新时期。该药已于 1998年经美国ＦＤＡ批准 ,正式应用于乳腺癌的治疗中 ,并取得了明显疗效 ,令人鼓舞。现就ＨＥＲ 2 /ｎｅｕ基因的检测及…     

腺病毒E1A下调HER2/neu原癌基因表达及其抗瘤效应研究

目的　研究腺病毒E1A基因对HER2 /neu高表达肿瘤细胞生长的抑制作用及增强其化疗敏感性的作用。方法　以腺病毒Ⅴ型为载体 ,经体、内外对HER2 /neu高表达及低表达的肿瘤细胞株转染腺病毒E1A基因后 ,观察E1A基因对肿瘤细胞生长抑制作用 ;用MTT法检测E1A增强肿瘤细胞化疗敏感性作用。结果　E1A能显著抑制HER2 /neu高表达的肿瘤细胞在体内外的生长 ,延长荷瘤裸鼠的生存期。免疫印迹及免疫组织化学分析显示 ,转染E1A的HER2 /neu高表达肿瘤细胞 ,其HER2 /neu基因产物p185蛋白表达明显降低 ;经AdE1A 处理的HER2 /neu高表达的乳腺癌细胞株能明显增强对TaxotereTM的化疗敏感性。结论　E1A通过下调HER2 /neu原癌基因的表达 ,抑制HER2 /neu高表达的肿瘤细胞生长 ,增强肿瘤细胞对化疗药的敏感性。     

胃癌组织Her-2/neu与TopoⅡα的表达及临床意义

目的：探讨Her-2／neu、TopoⅡα在胃癌组织中的表达及临床意义。方法：应用免疫组织化学PV-9000方法检测90例胃癌及30例正常胃组织中Her-2／neu、TopoⅡα的表达情况，分析二者的表达与临床病理特征之间的关系。结果：90例胃癌组织和30例正常胃组织中Her-2／neu阳性表达率分别为20．0％和3．3％（P〈0．05），TopoⅡα阳性表达率分别为65．6％、86．7％（P〈0．05）。胃癌组织Her-2／neu的过表达与胃癌的Lauren分型、分化程度、淋巴转移显著相关。胃癌组织中TopoⅡα阳性表达仅与肿瘤的分化程度相关。在18例Her-2／neu高表达的胃癌中有72．2％（13／18）伴有TopoⅡα的表达，在77例TopoⅡα阳性表达的组织中有16．9％（13／77）伴有Her-2／neu的过表达。结论：Her-2／neu、TopoⅡα在胃癌组织表达增高与胃癌的发生发展密切相关，联合检测Her-2／neu、TopoⅡα对于胃癌的治疗具有指导意义，也是判断预后的重要指标。     

Faslodex治疗ER阳性原发性乳腺癌中HER—2扩增状态在抗增殖反应中的影响

大约 1 0 %的乳腺癌雌激素受体 (ER)及人类表皮生长因子受体 2 (HER 2 )同时阳性。大量临床证据证实此类乳腺癌对三苯氧胺治疗效果差。三苯氧胺耐药部分原因是由于HER 2与ER信号传导通路的交叉 ,导致对三苯氧胺激动效应增强。Faslodex(Fulves trant)是新型ER拮抗剂 ,可下调ER水平 ,无激动效应 ,在ER(+)、HER 2阳性患者中可能比三苯氧胺更有效。将绝经后术前组织学证实的原发性乳腺癌患者随机分 3组 :①Faslodex(5 0mg、1 2 5mg、2 5 0mg)肌注 ;②三苯氧胺 2 0mg d ,连续 1 4～ 2 1天 ;③安慰剂每日 1次口服 ,连续 1 4～ 2 1天。治…     

TOPⅡa基因扩增对蒽环类药物在HER2阳性乳腺癌新辅助化疗中的疗效预测

目的:研究TOPⅡa基因扩增对蒽环类药物在HER2阳性乳腺癌新辅助化疗中对于疗效的预测作用。方法:选择我院2007-2010年间216例HER2阳性乳腺癌新辅助化疗患者,均给予TAC（多西他赛+吡柔比星+环磷酰胺）方案进行化疗。依据TOPⅡa基因扩增状态将患者分为扩增组与非扩增组,对比组间客观有效率及病理完全缓解率差异。结果:HER2为3+者的客观有效率及病理完全缓解率优于2+/1+者。TOPⅡa基因扩增患者的ORR及pCR%显著优于非扩增组（74.6% vs.21.5%,38.8% vs.2.7%,P<0.001）。亚组分析中发现,在HER2表达一定时,TOPⅡa基因扩增情况对以蒽环类为基础的新辅助化疗方案的疗效仍具有预测作用。结论:HER2阳性乳腺癌对蒽环类有良好的临床疗效可能归因于肿瘤组织中TOPⅡa基因的扩增。     

计算机辅助设计HER2/neu酪氨酸激酶小分子抑制剂及其生物活性研究

目的：用计算机辅助设计法寻找HER2/neu受体酪氨酸激酶小分子抑制剂。方法：用MODERLAR软件模拟出HER2/neu和EGFR受体酪氨酸激酶的三维(three dimensional,3D)空间结构;根据HER2/neu酪氨酸激酶ATP结合区的空间结构,搜索数据库,找出候选化合物;用Westernblot方法检测化合物对HER2/neu受体酪氨酸激酶磷酸化的影响;MTT法检测细胞增殖抑制作用。结果：比较HER2/neu和EGFR（靶蛋白）与胰岛素受体酪氨酸激酶、FGFR1受体酪氨酸激酶和Src酪氨酸激酶（模板蛋白）的氨基酸序列发现有35％～41％的相同和52％～55％的相似,用MODELLER程序模拟出HER2/neu和EGFR激酶区域的3D结构。根据HER2/neu受体酪氨酸激酶结构模型,3D数据库的搜索,获得潜在HER2/neu酪氨酸激酶抑制剂化合物,经筛选、优化发现ST2325对HER2/neu磷酸化有明显的抑制作用,其IC50值为6.6μmol/L,且抑制作用是可逆的,对EGFR受体磷酸化没有抑制作用。ST2325对HER2/neu受体表达没有影响。ST2325对HER2/neu过表达的肿瘤细胞MDA MB 453m1的抑制作用更强,而对EGFR过表达的肿瘤细胞MDA MB 468抑制作用相对较弱,其IC50值分别为29.05μmol/L和60.40μmol/L。结论：基于HER2/neu的结构设计,筛选出对HER2/neu酪氨酸激酶有明显选择性抑制作用的ST2325。     

HER2阳性乳腺癌中p95HER2表达与细胞增殖的相关性研究

目的 通过检测并分析HER2阳性乳腺癌患者肿瘤组织中p95HER2的表达情况,探索其与相关临床及病理特征之间的关系,建立p95HER2过表达细胞验证其促进细胞增殖的生物学功能,为临床HER2阳性乳腺治疗提供实验基础。方法 收集2020年12月至2021年12月就诊于江苏省人民医院普外科的47例HER2阳性乳腺癌患者的肿瘤组织及其临床资料。通过免疫组化法检测肿瘤组织中p95HER2蛋白的表达水平,比较p95HER2阳性组及阴性组的临床病理及检验资料的组间差异。通过p95HER2慢病毒质粒表达载体转染BT474细胞,构建RT-qPCR和Western blot方法验证的p95HER2蛋白稳定表达的BT474-p95细胞株。以BT474-p95细胞株为模型,经过CCK8和克隆形成试验验证考察p95HER2蛋白表达对细胞曲妥珠单抗的敏感性及其对细胞增殖的影响。结果 47例HER2阳性乳腺癌患者肿瘤组织中,p95HER2的阳性率为44.7%(21/47)。p95HER2蛋白的表达情况与患者肿瘤的Ki67指标相关,差异有统计学意义(P<0.05);而p95HER2表达情况与患者的不同年龄、肿...     

Prevalence of hormone receptors and HER2/neu in breast cancer cases in Jordan

The management and prognosis of breast cancer nowadays require the evaluation of Estrogen (ER), Progesterone Receptors (PR) and HER2/neu. Ethnic variation in the expression of these receptors is well documented. The aim of this study is to determine the prevalence of ER, PR and HER2/neu among Jordanian women with breast cancer of ductal and lobular types. A retrospective analysis was performed on 267 cases of breast cancer referred for treatment at King Hussein Cancer Center, Jordan between the period of June 2003 and June 2004. Standard immune stains were used for evaluation of hormone receptors and HER2/neu. In addition, evaluation of HER2/neu was done by FISH in selected cases. Of these 267 cases, 240 (89.9%) were ductal carcinomas of various histological grades, 122 (50.8%) of which were ER-positive, 138 (57.5%) PRpositive and 42 (17.5%) HER2/neu-positive. Twentytwo (8.2%) of all cases were lobular carcinomas, 15 (68%) of which were ER-positive, 20 (90.9%) PRpositive and 3 (13.6%) HER2/neu-positive. Five (1.9%) of the total cases were of mixed lobular and ductal types, 4 (80%) of which were ER-positive, 3 (60%) PR-positive and none were positive for HER2/neu. The prevalence of hormone receptor positivity in breast cancer of Jordanian women is lower than that of the western populations and close to other populations such as the Chinese and the minor ethnic groups of Northern America (African Americans).     

Influences of apolipoprotein E polymorphism on the risk for breast cancer and HER2/neu status in Taiwan

Summary Apolipoprotein E (APOE) polymorphism plays an important role in lipid metabolism. Preliminary evidence suggests that APOE genotype appears to be a risk factor for not only cardiovascular disease, but also Alzheimers disease and cancer. We screened the APOE genotype in 290 breast cancer patients and 232 non-cancer controls and determined the relationship between APOE gene polymorphism and breast cancer in Taiwan. We found risk for breast cancer was associated with the APOE genotype (² = 8.652, p = 0.013). Carriers of the 4 allele were more common in breast cancer cases than carriers of 3 allele (p = 0.004, OR = 1.786, 95% CI: 1.197–2.664). In addition, the 4 allele is also associated with HER2/neu negative status in breast cancer patients (p = 0.006, OR = 0.277, 95% CI: 0.111–0.693). No significant associations between APOE genotype and tumor grade, TN classification, progesterone receptor, estrogen receptor, lymphatic invasion, or recurrence of breast cancer were in evidence. These results suggest that the APOE 4 allele may be a risk factor for breast cancer and correlates with HER2/neu negative status.     

TOP2A amplification in the absence of that of HER-2/neu: toward individualization of chemotherapeutic practice in breast cancer

Primary objective.

To investigate the relationship between human epidermal growth factor receptor (HER)-2/neu and the gene encoding topoisomerase IIα (TOP2A) in breast cancer, while elucidating their association with clinicopathological variables.

Methods.

Real-time quantitative polymerase chain reaction (RQ-PCR) was performed on a 96-patient study group to assess gene amplification, and levels were determined using the comparative cycle threshold approach and Taqman assays. An immunohistochemistry (IHC) microarray (n = 76) was then employed to check for correlation between gene amplification and protein expression levels.

Results.

Amplification levels of TOP2A did not differ significantly according to HER-2/neu status by either RQ-PCR or IHC microarray. Of the HER-2/neu⁻ patients, 29.1% demonstrated levels of TOP2A above the third quartile, whereas 22.9% of the HER-2/neu⁺ patients had values in the first quartile (log TOP2A <0.62), thereby indicating low-level amplification. Of the 60 patients characterized as HER-2/neu⁻ using IHC and fluorescence in situ hybridization (FISH), 22.9% were classified as TOP2A⁺ on the IHC microarray. Of the 14 patients deemed HER-2/neu⁺ using IHC and FISH, meanwhile, the majority (n = 10) were classified as TOP2A⁺.

Conclusions.

Our results indicate that amplification of TOP2A in breast cancer is not confined to those who are concomitantly HER-2/neu⁺, and suggest that a significant proportion of HER-2/neu⁻ patients exhibit high levels of TOP2A.     

Correlation of p27 protein expression with HER-2/neu expression in breast cancer

Strong expression of human epidermal growth factor receptor 2 (HER-2)/neu in breast cancer has been associated with poor prognosis. Reduced expression of p27(Kip1), a cyclin-dependent kinase inhibitor, correlates with poor clinical outcome in breast cancer. In this study, we provide a correlation between these two important prognostic markers in patients with breast cancer. Breast tumor screening using immunohistochemistry indicated that downregulation of p27 correlated with HER-2/neu overexpression in studying 11 normal breast tissues and 51 primary breast carcinomas. We found HER-2/neu protein overexpression in 20 (41%) of 49 breast cancers and low p27 protein expression in 47 (92%) of 51 breast cancers. All 20 (100%) of the tumors that overexpressed HER-2/neu had low levels of p27 protein product; this correlation was statistically significant (P = 0.035). Decreasing p27 expression correlated with increasing HER-2/neu activity. Our results suggest that one function of the HER-2/neu product is to downregulate p27 expression in breast cancer. This study may be significant in selecting patients for HER-2/neu antibody therapy in the future. Mol. Carcinog. 30:169--175, 2001.     

HER2/neu基因扩增和蛋白表达与晚期胃癌患者预后的关系

背景与目的:有证据表明胃癌患者HER2/neu过表达与预后不良及高侵袭性相关,本研究旨在探求HER2/neu表达与晚期胃癌患者临床特征,尤其是与生存期的关系。方法:回顾性分析2006～2008年中国医学科学院肿瘤医院收治的83例晚期胃癌患者的临床资料。应用免疫组化(IHC)和荧光原位杂交(FISH)法检测83例患者的HER2/neu表达情况。数据分析采用SPSS13.0统计软件,生存分析应用Kaplan-Meier法,生存率比较采用log-rank检验。结果:83例患者中位年龄60岁,男女比例为2.95:1。存在HER2/neu蛋白过表达(2+和3+)和基因扩增的患者分别为25例(30.1%)和29例(34.9%)。存在HER2/neu蛋白过表达和基因扩增的晚期胃癌患者往往预后不佳。无HER2/neu基因扩增的晚期胃癌患者中位生存期12.6个月,而有基因扩增者中位生存期仅5.5个月。结论:HER2/neu的表达情况对判断晚期胃癌预后有一定临床意义。     

Her-2/neu amplification determined by real-time quantitative PCR and its association with clinical outcome of breast cancer in Thailand

HER-2/neu has been found to be amplified or overexpressed in about 20-30% of breast cancers, in association with negative prognosticators and shortened survival. Determination of HER-2/neu status in breast-cancer patients, to select for adjuvant treatment with trastuzumab, is becoming standard breast-cancer clinical practice. This study aimed to investigate HER-2/neu status in breast-cancer by real-time quantitative polymerase chain reaction (PCR), allowing accurate and precise quantification of HER-2/neu amplification in tumor tissues. We evaluated 112 breast-cancer samples, of which 42 (37.5%) had HER-2/neu amplification. After a mean follow-up period of 71 months, HER-2/neu amplification was found to be significantly associated with increased risk of death (HR = 6.367, 95% CI = 1.787-22.684), even after adjusting for age, clinical stage, tumor size, lymph-node status, and histologic grade. These findings support a negative prognostic role for HER-2/neu in breast-cancer survival. We suggest that real-time quantitative PCR analysis of HER-2/neu amplification represents an alternative technique for establishing HER-2/neu status in routine clinical practice.     

Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients

Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser-473. Eighty-four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p = 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease-free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy.     

Hormone receptors do not predict the HER2/neu status in all age groups of women with an operable breast cancer.

BACKGROUND: In breast cancer, there is an inverse relationship between HER2/neu overexpression and receptors for estrogen (ER) or progesterone (PR). Some clinical observations such as the age-related association between hormone receptors and tumour grade, which predicts HER2/neu overexpression, suggest an age-related relationship. PATIENTS AND METHODS: Our study population consisted of 1362 consecutive women receiving primary surgery for non-metastatic invasive breast cancer. We compared the relationship between both hormone receptors and HER2/neu overexpression in different age groups taking other tumour characteristics into account. RESULTS: In a multivariate model, considering the overall group, a negative ER, a negative PR and a high tumour grade were predictive for HER2/neu overexpression (P <0.001). Considering 246 women aged < or =45 years, the only predictor for HER2/neu overexpression in this age category was a high tumour grade (P = 0.003). Considering the 1116 women aged >45 years, ER (P = 0.001), PR (P = 0.001) and tumour grade (P <0.001) were associated with HER2/neu (P <0.001). CONCLUSION: Our findings indicate that the association between ER, PR and HER2/neu overexpression varies with age. The hormone receptors are not an independent predictor for the HER2/neu status in young women while they are in elder patients.     

Topoisomerase II-alpha gene deletion is not frequent as its amplification in breast cancer

Summary Topoisomerase II-alpha (TOP2A) has been investigated as a potential predictor for the response to doxorubicin-based chemotherapy which is a representative TOP2A inhibitor and one of the most effective chemotherapeutics for the breast cancer treatment. We performed the assay for the TOP2A gene amplification and deletion on a tissue microarray (TMA) of 284 breast tumor samples from the patients treated by doxorubicin-based adjuvant chemotherapy. TOP2A gene was deleted in six patients (2.1%), whereas TOP2A gene was amplified in 20 (7.1%) of 284 tumors. Twenty-four of 26 TOP2A amplifications and deletions were associated with HER2 co-amplification. TOP2A amplification or deletion was not associated with poor clinical outcome. Nine (34.6%) of 26 patients with TOP2A amplification or deletion had recurrent disease. Thirty percent of the patients with TOP2A amplification had systemic recurrence whereas 50% of the patients with TOP2A deletion had systemic recurrence. On multivariate analysis, histologic grade and tumor size were the significant predictors for the disease-free survival and histologic grade was an only significant predictor for the overall survival. Our study indicates that response to the doxorubicin-based chemotherapy might be stratified by TOP2A amplification and deletion. However, relative low frequency of TOP2A genetic changes seems to hamper its clinical utility.