Ｋｉ-６７、ＥＧＦＲ、ＨＥＲ-２和ｐ５３在乳腺癌中的表达及其相关性

目的　分析Ｋｉ-６７、ＥＧＦＲ、ＨＥＲ-２、ｐ５３在乳腺癌组织中的表达,并探讨其与乳腺癌临床病理特征之间的相关性。方法　用免疫组化法检测１３８例乳腺癌患者病理组织中Ｋｉ-６７、ＥＧＦＲ、ＨＥＲ-２和ｐ５３蛋白的表达,并结合临床病理特征进行相关性分析。结果　Ｋｉ-６７、ＥＧＦＲ、ＨＥＲ ２和ｐ５３在乳腺癌组织中的表达率依次为９１.３０％、１７.３９％、６２.３２％和２３.１９％,不同年龄组其表达均无统计学差异（Ｐ＞０.０５）。Ｋｉ-６７的表达与组织学分级、病理类型、肿块大小、淋巴结是否转移及分期显著相关（Ｐ＜０.０５）;ＥＧＦＲ表达与病理类型和ＥＲ状态显著相关（Ｐ＜０.０５）;ＨＥＲ ２表达与病理类型、组织学分级、淋巴结转移、远处转移及分期无相关性（Ｐ＞０.０５）;而ｐ５３表达与组织学分级、ＥＲ和ＰＲ状态呈显著相关（Ｐ＜０.０５）。ＥＲ和ＰＲ呈正相关;ＥＧＦＲ、ＨＥＲ-２、ｐ５３与ＥＲ均为负相关;ＨＥＲ-２和ＰＲ呈负相关;Ｋｉ-６７与ＥＧＦＲ、ＨＥＲ-２、ｐ５３、ＥＲ及ＰＲ之间均无相关性;ｐ５３与ＥＧＦＲ呈正相关;ＥＧＦＲ与ＨＥＲ-２呈负相关。结论　联合检测乳腺癌组织中ＥＧＦＲ、Ｋｉ-６７、ＨＥＲ-２和ｐ５３蛋白的表达能更清楚地了解乳腺癌的生物学行为,对乳腺癌的诊断、指导治疗及评价预后有重要的临床意义。     

治疗转移性乳腺癌的新药--Herceptin

Ｈｅｒｃｅｐｔｉｎ（荷塞停）是一种针对ＨＥＲ－２基因产物Ｐ１８５的单抗,由于其对ＨＥＲ过表达的晚期乳腺癌有特殊疗效而获美国ＦＤＡ批准上市,其单药有效率约１０％－１４％,联合化疗药物有效率达５０％,能延长病人生存期且毒副反应轻微,是一种很有发展前景的治疗晚期乳腺癌药物。     

自制抗p185c-erbB-2单克隆抗体的应用研究

癌基因ｃ -ｅｒｂＢ -２的扩增及其产物 ｐ１８５ｃ -ｅｒｂＢ -２（ｐ１８５）的过度表达与多种肿瘤 (如乳腺癌、卵巢癌、肺癌、膀胱癌、胃癌等 )的发生发展密切相关 ,而且ｐ１８５表达尚与肿瘤的预后、复发及患者生存期有一定关系 ,也与肿瘤对治疗的敏感性相关 ,同时 ｐ１８５也被认为是肿瘤特异性治疗的靶目标。因此 ,针对癌基因蛋白 ｐ１８５的研究已成为肿瘤诊断、治疗的又一途径。为了进一步研究ｐ１８５在肿瘤发生过程中的致癌机制以及作为肿瘤治疗的靶分子的可能性 ,本文利用在国内首先成功研制的抗ｐ１８５单克隆抗体（ＭｃＡｂ）…     

乳腺癌之c—erbB—2高度扩增,表达与雌孕激素受体的相关性

用自制抗ｐ１８５ＭｃＡｂ－５Ｅ１２和进口抗ｐ１８５ＭｃＡｂ（ｃ－ｎｅｕＡｂ－３）以免疫组化法对５７例原发性乳腺癌组织的ｐ１８５表达情况进行对比研究，并以ＤＣＣ法测定其雌孕激素受体水平，对其中３４例乳腺癌组织提取ＤＮＡ进行ｃ－ｅｒｂＢ－２的Ｓｏｕｔｈｅｒｎｂｌｏｔ分析。观察ｃ－ｅｒｂＢ－２癌基因扩增与蛋白表达水平及其与雌孕激素受体水平之间的相关性。结果显示免疫组化法测定ｐ１８５蛋白表达与Ｓｏｕｔｈｅｒｎｂｌｏｔ测定基因扩增的结果个例对应的阴阳性符合率为９４．１％（３２／３４），５Ｅ１２和进口ｃ－ｎｅｕＡｂ－３的个例对应阴阳性符合率为９６．５％（５５／５７），另外，ｐ１８５表达水平雌孕激素受体呈负相关。结果表明ｃ－ｅｒｂＢ－２蛋白产物ｐ１８５表达水平基本可以反映基因ｃ－ｅｒｂＢ－２扩增水平的变化；同时，也说明５Ｅ１２有良好的特异性和灵敏性，已达进口ＭｃＡｂ水平。     

Herceptin治疗乳腺癌的临床研究进展

Ｈｅｒｃｅｐｔｉｎ是近年新研制的人源性单克隆抗体,它通过与细胞表皮生长因子受体ＨＥＲ２蛋白特异性结合,抑制ＨＥＲ２过度表达的乳腺癌细胞生长。目前国外已完成Ｈｅｒｃｅｐｔｉｎ治疗乳腺癌的临床Ⅲ期试验。结果显示,该药对ＨＥＲ２过度表达的乳腺癌患者效肯定,联合化疗可显著延长患者生存期;其毒副作用轻微,主要为心脏毒性。     

乳腺癌p53、c－erbB－2基因蛋白、表皮生长因子受体与雌、孕激素受体的表达及其临床意义

应用免疫组化ＡＢＣ法检测１００例乳腺癌和１００例乳腺良性病变组织中ｐ５３、ｃ－ｅｒｂＢ－２、ＥＧＦＲ与ＥＲ、ＰｇＲ的表达。结果显示：乳腺癌各种标记阳性率均高于乳腺良性病变；ＥＲ阳性率在５０岁以上组高于５０岁以下组（Ｐ＜０．０５）；不同病理学类型中各种标记的阳性率亦存在一定差异，乳腺癌中ｐ５３、ｃ－ｅｒｂＢ－２、ＥＧＦＲ和ＥＲ及ＰＲ的表达呈显著负相关（Ｐ＜０．０１），可能成为判断乳腺癌治疗和预后的重要标志。     

Herceptin对转移性乳腺癌的靶向治疗作用

转移性乳腺癌是一种慢性疾病 ,化疗和 (或 )内分泌治疗为目前主要控制疾病进展的方法 ,但仍有部分患者疾病发展快 ,预后差 ,对化疗及三苯氧胺抗拒 ,缺乏有效治疗手段。近来 ,通过对乳腺癌的生物学特性进一步了解 ,发现编码生长因子受体的原癌基因ＨＥＲ 2在肿瘤发生发展中起重要作用。Ｇｅｎｅｎｔｅｃｈ公司开发的针对ＨＥＲ 2的抗体—Ｈｅｒｃｅｐｔｉｎ ,现已通过美国ＦＤＡ批准上市 ,可用于乳腺癌的临床治疗。一、ＨＥＲ 2简介ＨＥＲ 2 (ｈｕｍａｎｅｐｉｄｅｒｍａｌｇｒｏｗｔｈｆａｃｔｏｒｒｅｃｅｐｔｏｒ2 ,ＨＥＲ 2 )是相对分子…     

大肠癌p185^erbB2,p21^ras,p53的表达及其临床病理意义

目的：研究大肠癌中ｐ１８５＾ｅｒｂＢ２、ｐ２１＾ｒａｓ、ｐ５３的表达及其临床病理意义。方法采用Ｓ－Ｐ法检测８０例大肠癌组织中ｐ１８５＾ｅｒｂＢ２、ｐ２１＾ｒａｓ、ｐ５３的表达。结果大肠癌原发病灶中ｐ１８５＾ｅｒｂＢ２、ｐ２１＾ｒａｓ、ｐ５３的阳性表达率分别为５８．８％、７１．３％及５３．８％。癌组织同时有２种以上蛋白表达者占６３．７％（５１／８０）,有３种蛋白同时表达者占３０％（２４／８０）。ｐ１     

HER2／neu基因介导的信号传递及其在肿瘤免疫中的作用

ＨＥＲ２／ｎｅｕ是一种跨膜生长因子受体基因，编码的１８５ｋＤ糖蛋白具有肥体酪氨酸激活性，ＨＥＲ２／ｎｅｕ基因的扩增或蛋白的过度表达可通过活化信呈传递系统而诱导的细胞恶变，针对ＨＥＲ２／ｎｅｕ蛋白的单克隆抗体可模拟或阻断配体的生物学功能而发挥促进或抑制肿瘤生长效应。对细胞生长的信号传递系统的深入了解不但有助于肿瘤发生机理的研究，而且为寻找有效的抗肿瘤方法提供了一条新的思路。     

不同ＥＲ状态乳腺癌组织Ｂｃｌ-２的表达及其临床意义

目的　分析不同ＥＲ状态的乳腺癌组织中Ｂｃｌ-２表达情况及其意义。方法　采用免疫组织化学方法检测１６０例浸润性乳腺癌组织中ＥＲ和Ｂｃｌ-２的表达情况,依据ＥＲ状态分为ＥＲ阳性和阴性组,分别比较Ｂｃｌ-２表达与临床病理特征的关系。结果　１６０例乳腺癌组织中ＥＲ阳性为７０例（４３.８％）,Ｂｃｌ-２阳性７４例（４６.３％）,Ｂｃｌ-２与ＥＲ表达呈正相关。ＥＲ阳性组中Ｂｃｌ-２表达与淋巴结转移少、组织学分级低及临床分期早显著相关,ＥＲ阴性组中Ｂｃｌ-２表达与上述临床病理特征均无关。结论　乳腺癌组织中存在Ｂｃｌ-２表达,其中ＥＲ阳性乳腺癌组织中Ｂｃｌ-２表达与临床病理特征有相关性。     

Recent Progress in HER2 Associated Breast Cancer

Breast cancer is the most common cancer worldwide among women and the second most common cancer.Approximately 15-23% of breast cancers over-express human epidermal growth factor receptor2 (HER2), a185-kDa transmembrane tyrosine kinase, which is mainly found at the cell surface of tumor cells. HER2-positivebreast cancer, featuring amplification of HER2/neu and negative expression of ER and PR, has the three followingcharacteristics: rapid tumor growth, lower survival rate, and better response to adjuvant therapies. Clinically,it is notable for its role in a pathogenesis that is associated with increased disease recurrence and acts as a worseprognosis. At the same time, it represents a good target for anti-cancer immunotherapy despite the prevalenceof drug resistance. New treatments are a major topic of research, and a brighter future can be expected. Thisreview discusses the role of HER2 in breast cancer, therapeutic modalities available and prognostic factors.     

Clinical usefulness of human epidermal growth factor receptor-2 extracellular domain as a biomarker for monitoring cancer status and predicting the therapeutic efficacy in breast cancer

We assessed the clinical usefulness of human epidermal growth factor receptor-2 extracellular domain (HER2ECD) as a biomarker for detecting cancer and monitoring disease status and for predicting the efficacy of anticancer treatment in breast cancer. Five-hundred and eighty serum samples from 252 patients with breast cancer were examined for the concentration of HER2ECD to compare with conventional tumor markers (CEA, CA15-3, NCC-ST439 and BCA225). Also, in 19 patients with HER2-overexpressed advanced or recurrent breast cancer who were treated with trastuzumab, clinical outcomes were evaluated retrospectively to determine whether their serum HER2ECD levels predict clinical responses. The proportion of patients with elevated HER2ECD levels was 15.1%, which was compatible with those with elevated conventional marker levels. In patients with HER2-overexpressed breast cancer, the positive rate of HER2ECD was significantly higher (24.1%) than those of conventional markers (7.4–12.9%), suggesting the usefulness of HER2ECD for detecting cancer in this population. HER2-overexpressed patients responding to trastuzumab (12 of 19 patients) showed significantly higher serum HER2ECD level (p = 0.033) and longer time to progression (TTP) (p = 0.039) and overall survival (OS) (p = 0.031) than did patients not responding (seven patients). Furthermore, higher response rates were observed in patients with elevated HER2ECD levels than in patients without elevated HER2ECD levels (91.3% vs. 14.3%, p = 0.032), whereas there was no difference in survival between the two groups. The results suggest that HER2ECD is a useful biomarker not only for detecting breast cancer recurrence but also for predicting tumor responses to trastuzumab.     

HER2 status in hormone receptor positive premenopausal primary breast cancer adds prognostic, but not tamoxifen treatment predictive, information

BACKGROUND: Overexpression of human epidermal growth factor receptor 2 (HER2) or amplification of its gene is a prognostic factor in primary breast cancer and a predictor for tamoxifen treatment efficacy in oestrogen receptor (ER) positive disease. In the present study we explored a defined cohort of breast cancer patients included in a randomised trial in order to assess prognostic and tamoxifen treatment information yielded by HER2 status. METHODS: Premenopausal breast cancer patients with stage II tumours (n = 564) were included and allocated to 2 years of adjuvant tamoxifen treatment versus no adjuvant treatment. ER, progesterone receptor (PR) status and HER2 status was determined by immunohistochemistry using a tissue microarray. HER2 amplification was analysed by fluorescent in situ hybridisation and tumours being amplified and/or HER2 3+ were considered HER2+. HER2 status was evaluable in 83% of the patients and 12.6% were HER2+. In untreated patients, HER2 was a negative prognostic factor in ER+ patients, HR 2.95; 95% CI: 1.61-5.38, p < 0.001, but not in ER- patients, HR 0.67; 95% CI: 0.28-1.61, p = 0.4, and a significant interaction between the two markers was found, p < 0.01. HER2 status was not related to tamoxifen treatment efficacy in ER+ patients (term of interaction p = 0.95). When stratifying for PR status, similar results were achieved. DISCUSSION: HER2+ and ER+ breast cancer constituted a subgroup of tumours with poor prognosis in premenopausal breast cancer, whereas no treatment interaction was found between HER2 status and tamoxifen in ER+ tumours. The poor prognosis in HER2+ and ER+ patients may interfere with the interpretation of HER2 data in non-randomised trials of adjuvant tamoxifen.     

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer.     

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。     

Estrogen-dependent,tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu

Summary Since the poor prognosis associated with HER2 amplified breast cancers might be explained by a mechanistic association between p185^HER2 overexpression and therapeutic resistance, we assessed the chemo-endocrine sensitivity of estrogen receptor (ER) containing MCF-7 breast cancer cells transfected with full-length HER2 cDNA. Of the 36 isolated MCF/HER2 subclones, 7 were found to overexpress p185^HER2 surface receptor at levels 3 to 45-fold greater than parental or control transfected cells (MCF/neo). The overexpressing transfectants possessed increased inositol-1,4,5-trisphosphate-3'-kinase activity comparable to enzyme activity in the endogenously HER2 amplified breast cancer cell lines SK-Br-3 and BT-474. The anti-p185^HER2 monoclonal antibody and receptor-specific partial agonist, muMAb4D5 (4D5), known to inhibit growth of SK-Br-3 and BT-474 cells, produced no significant growth inhibitory effect on any of the transfectants including the 45-fold overexpressing MCF/HER2–18 cells which were studied in greater detail. MCF/HER2–18 cells contained at least partially functioning exogenous receptor since 4D5 (3µg/ml) specifically stimulated phosphorylation of p185^HER2 and its co-precipitating ptyr56 substrate within 5 min, and this was followed at 1 h by a transient induction ofc-myc but notc-fos mRNA. ER content and thein vitro sensitivity of MCF/HER2–18 cells to 5-fluorouracil and adriamycin were identical to those of control transfectants and parental cells. However, these highly overexpressing transfectants had acquired low level (2 to 4-fold) resistance to cisplatin and were no longer sensitive to the antiestrogen tamoxifen (TAM). To compare the hormone-dependent tumorigenicity of the HER2 transfectants, MCF/HER2–18 and control cells (MCF, MCF/neo-3) were implanted into ovariectomized athymic nude mice. No tumors were produced in the absence of estradiol (E₂) administration. In E₂ supplemented mice, MCF/HER2–18 tumors grew most rapidly. When E₂ treatment was stopped and daily TAM injections were initiated, MCF-7 and MCF/neo-3 tumor growth ceased immediately, while MCF/HER2–18 tumors continued to show an accelerated growth rate lasting weeks. This pattern of hormone-dependent, TAM-resistant growth exhibited by the MCF/HER2–18 tumors in nude mice supports the possibility that p185^HER2 overexpression in human breast cancers may be linked to therapeutic resistance.     

Trastuzumab (Herceptin) in the treatment of breast cancer with HER2 overexpression

HER2 is a 185 kDa transmembrane receptor with tyrosine kinase activity encoded by the HER2/neu gene. HER2 is overexpressed in 25%–30% of breast cancer and confers an agressive clinic course. Trastuzumab (Herceptin) is a monoclonal antibody directed against HER2 receptor that has a favorable toxicity profile and produces responses as a single agent in women with metastatic breast cancer with HER2 overexpression. A multicenter phase III trial in HER2 positive metastatic breast cancer, compared first line chemotherapy with adriamycin/cyclophosphamide or paclitaxel alone or the same chemotherapy plus trastuzumab. Response rate, duration of response and time to progression, were better with the combination. Remarkably, overall survival was significantly improved in patients with trastuzumab and chemotherapy. These studies led to the approval of trastuzumab for HER2 positive metastatic breast cancer. Ongoing trials are analyzing new combinations of trastuzumab and chemotherapy or hormonal therapy. The role of trastuzumab in adjuvant and neoadjuvant therapy is also under investigation.      

MUC1与HER2基因在乳腺癌中的研究进展

乳腺癌发病趋势逐年升高,近年来研究发现,MUC1、HER2基因的表达水平能反映乳腺癌的某些生物学特征,与乳腺癌的发生、转移、预后等关系密切.MUC1基因在乳腺癌组织中出现质和量的异常表达.MUC1基因的编码产物成为十分重要的癌标志物,并且是检测乳腺癌淋巴结微小转移的指标.HER2基因在肿瘤组织中呈现过度表达,在正常组织中表达水平较低,被认为是判断乳腺癌预后的独立标记物,其高表达提示乳腺癌细胞的高转移潜能,表现出较高的侵袭性临床病理特征.随着研究的深入,在乳腺癌基因靶点治疗方面也取得了巨大的进展.针对HER2的基因靶点治疗已日趋成熟,Herceptin目前已被证实在乳腺癌的治疗中有巨大的应用前景.MUC1的基因靶点治疗尚处于试验阶段.本文从基因定位、结构、执行功能的分子机制角度对MUC1,HER1在乳腺癌中的作用进行了总结,以便更深入的认识这些基因及其表达产物的生理和病理生理作用,利于乳腺癌的诊断和治疗.     

HER2低表达乳腺癌的临床研究进展

乳腺癌是全球发病率最高的恶性肿瘤,严重影响女性的健康。人表皮生长因子受体2(Human epidermal growth factor receptor 2,HER2)作为乳腺癌重要的治疗靶点,对应的靶向治疗改善了此类患者的预后。在既往的诊治过程中,HER2低表达乳腺癌被归类为HER2阴性乳腺癌的范畴。随着研究的不断深入,发现HER2低表达乳腺癌患者在临床病理、分子生物学特征和生存预后等方面具有一定差异,并且难以从传统的抗HER2治疗中获益。多项研究探索了抗体药物偶联物(Antibody-drug conjugates, ADC)以及其他新型药物在HER2低表达乳腺癌中的疗效及安全性。本文将针对HER2低表达乳腺癌相关研究进展进行综述。     

曲妥珠单抗治疗1 8 5例HER2阳性乳腺癌患者的心脏安全性评价

 目的 探讨HER2阳性乳腺癌患者应用曲妥珠单抗治疗的心脏安全性。方法 185例HER2阳性乳腺癌患者接受每3周一次的曲妥珠单抗治疗,首次以负荷剂量8 mg/kg给药,此后每3周给予6 mg/kg静脉滴注,接受治疗4~36周期,观察其心脏安全性。结果 接受曲妥珠单抗治疗的HER2阳性乳腺癌患者中位治疗周期数为17个（4~36个）,88例（47.6%）出现LVEF下降、74例（40.0%）出现瓣膜反流（新增+加重）、16例（8.0%）出现左室舒张功能下降。发生心脏毒性88例（47.6%）,其中Ⅰ级心脏毒性83例、Ⅱ级心脏毒性5例,未见Ⅲ级心脏毒性发生。结论 曲妥珠单抗对HER2阳性乳腺癌患者心脏功能有一定影响,总体安全性良好。但是,在治疗中仍需注意评估与监测。