胃癌中Cks1 、p27 Kip1和Skp2 蛋白的表达

 目的 探讨Cks1在胃癌发生及其在Skp2调节p27 ^Kip1降解过程中的作用。方法 应用流式细胞术测定正常胃粘膜和胃癌组织中Cks1、p27^Kip1、Skp2蛋白表达。结果胃癌组织中Cks1、Skp2表达明显高于正常胃粘膜（x²=22．69，P〈0．05；x²=13．42，P〈0．05），而p27 ^Kip1表达则低于正常胃粘膜（x²=14．83，P〈0．05）。胃癌中Cks1、Skp2表达与p27 ^Kip1表达呈负相关（r=-0．649，P〈0．05；r=-0．732，P〈0．05）；而Cks1蛋白表达与Skp2蛋白缺乏相关性（P〉0．05）。胃癌中Cks1的表达与肿瘤分化程度相关（x²=5．05，P〈0．05），而与肿瘤浸润深度、淋巴结转移及临床分期不相关（P〉0．05）。结论Cks1可能参与了胃癌的发生；胃癌中Cks1可能参与了Skp2调节p27 ^Kip1泛素化降解过程。     

乳腺癌中cyclinD2 、CDK4 的表达及其临床意义

 目的 研究乳腺癌组织中细胞周期蛋白D2（cyclinD2）、细胞周期蛋白依赖性激酶4（cyclin-dependentkinase4,CDK4）的表达,探讨它们与p27^kip1蛋白表达、与临床病理指标的关系及其预后意义。方法 应用免疫组化SP法,检测96例乳腺癌、18例癌旁正常乳腺组织石蜡切片中cyclinD2、CDK4的表达,比较它们与p27 ^kip1蛋白表达、与临床病理学指标之间的关系。结果 ①96例乳腺癌组织中cyclinD2、CDK4和p27^kip1表达率分别为41.7％、54．2％和38．5％,与正常乳腺组织相比有显著性差异（P〈0．001）。②cyclinD2、CDK4的表达与乳腺癌的组织学分级,核分裂数有关（P〈0．001）,和局部复发有关（P〈0．05）,而与患者年龄、肿瘤大小、组织类型无关（P〉0．05）,CDK4的表达与乳腺癌的淋巴结转移,雌激素受体状态也有密切关系（P〈0．01）。③p27^kip1的表达缺失,与肿瘤大小、组织学分级,核分裂数,有无淋巴结转移以及局部复发均有关系（P〈0．05）,而且p27 ^kip1的表达与eyelinD2、CDK4的表达呈显著负相关（P〈0．叭）。结论 cyclinD2和CDK4的表达与乳腺癌的发生、发展有关,而p27 ^kip1的表达缺失和CDK4的异常表达与乳腺癌的侵袭、转移及复发有关,可作为判断乳腺癌生物学行为和预后的重要指标。     

乳腺癌组织中雌激素受体亚型ERβ的表达及其与临床病理指标的关系

 目的 研究乳腺癌组织中雌激素受体亚型ERB的免疫组织化学表达情况及其与临床病理指标的关系。方法 应用免疫组织化学方法检测327例乳腺癌组织中ERB和ERa及VEGF与c-erbB2的表达水平，对其进行比较研究，并结合月经状况、肿瘤大小、TNM分期、组织学类型、淋巴结转移等进行分析。结果 ERl3在原发性乳腺癌组织中的阳性表达率为20．49％（67／327），其表达与ERa的表达无相关性（r=-0．051，P=0．137），但与VEGF和c-erbB2的表达呈正相关（r=0．564，P=0．000；r=0．288，P=0．000）。腋窝淋巴结转移数大于3个者其原发肿瘤的ERp阳性率为31．8％，明显大于无转移者（χ²=4．436，P=0．035）和转移数小于等于3个者（χ²=6．369，P=0．012），后两组比较无统计学差异（χ²=0．744，P=0．388）。结论 ERβ与乳腺癌的发展有一定关联，可作为判断乳腺癌生物学行为的重要指标。     

c-erbB-2和nm23蛋白在乳腺癌中的表达及其临床意义

目的：探讨c-erbB-2和nm23在乳腺癌中的表达及其与临床预后因素的关系。方法：采用免疫组织化学S-P法检测70例原发性乳腺癌c-erbB-2和nm23蛋白表达,分析其表达水平与乳腺癌病理参数的关系。结果：c-erbB-2蛋白的阳性表达率为45．7％,与年龄、肿瘤大小无明显相关（P〉0．05）,与腋淋巴结转移及临床分期呈明显正相关（P〈0．05）。在组织学分级的比较中,高分化患者阳性率低,中低分化患者c-erbB-2蛋白表达阳性率高,有显著性差异（P〈0．05）,但中低分化患者之间无明显差异（P〉0．05）。nm23蛋白的阳性表达率为68．6％,与临床分期、组织学分级及腋淋巴结转移呈显著负相关,与年龄及肿瘤大小无明显关系。c-erbB-2表达与nm23表达两者之间呈明显负相关（P〈0．05）。结论：联合检测乳腺癌组织中c-erbB-2和nm23表达来估计患者预后指导意义更佳。     

乳腺浸润性导管癌中cyclinD1 、p57 KIP2的表达及意义

 目的 研究cyclinD1、p57^KIP2在乳腺浸润性导管癌（IDC）中的表达及意义。方法 采用免疫组织化学SP法检测64例113（2、15例乳腺导管内癌（DCIS）和15例癌旁正常乳腺组织中cyclinD1、p57 ^KIP2的表达。结果 cyclinD1、p57 ^KIP2阳性表达率在IDC与在乳腺不同组织之间、腋窝淋巴结有无转移之间差异均有显著性（P≤0．05，P〈0．01）；cyclinD1阳性表达率与IDC组织学分级有关（P〈0．01）；cyclinD1与p57 ^KIP2之间阳性表达率呈负相关（P〈0．01）。结论 cyclinD1与p57 ^KIP2共同参与了乳腺癌的发生发展过程。cyclinD1异常表达是乳腺癌发生的早期事件。联合检测cyclinD1及p57 ^KIP2对预测乳腺癌淋巴结转移有重要意义。     

组蛋白酶和c-erbB-2在乳腺癌中的表达

目的探讨乳腺癌病人c-erbB．2和cath-D表达与临床病理及预后的关系。方法通过免疫组化法，检测128例乳腺癌病人的c-erbB-2和cath-D的表达。结果cath-D和c-erbB-2表达与肿块大小、淋巴结转移显著相关（P〈0．0001）。c-erbB-2表达比不表达病人预后差（P=0．01）。结论c-erbB-2阳性表达和cath-D阳性表达者，恶性程度高，易转移、预后差。     

靶向HER-2 mRNA 反义硫代寡核苷酸体外抗乳腺癌活性研究

 目的 研究以HER2 mRNA为靶点的反义硫代脱氧寡核苷酸（S-ODNs）HA6722对HER-2过表达乳腺癌细胞株MDA-MB-453体外增殖的抑制作用，及HA6722对肿瘤细胞HER-2表达的影响。方法 选择HER2过表达的MDA-MB-453细胞与HER2低表达的MDA-MB-231细胞，MTT法观察S-ODNs对肿瘤细胞增殖的影响，免疫细胞化学（ICC）与RT-PCR方法研究S-ODNs对细胞HER2蛋白及mRNA表达的影响。结果 HA6722可以剂量依赖方式抑制MDA-MB-453细胞的体外增殖，IC50值（41．8±8．1nmol·L^-1，n=5，mean±s）显著低于对照序列Scramble6722（IC50=489．4±12．1nmol·L^-1，n=5，P〈0．01）。HA6722在蛋白水平与mRNA水平显著抑制MDA-MB-453细胞中HER-2的表达；HA6722对MDA-MB-231细胞的体外增殖无显著影响（IC50=476．7±17．6nmol·L^-1，n=5，P〉0．05）。结论 HA6722可序列特异性地抑制HER-2过表达乳腺癌细胞的体外增殖，其抑制增殖作用与靶细胞HER-2表达下调有关。     

乳腺癌组织中拓扑异构酶Ⅱa和环氧合酶-2的表达及其临床意义

目的探讨拓扑异构酶Ⅱa【（TopoⅡa）和环氧合酶-2（COX-2）在乳腺癌组织中的表达及其与临床病理特征的关系。方法采用免疫组织化学法检测50例乳腺癌组织中TopoⅡa和COX-2的表达。结果TopoⅡa在乳腺癌及其周围正常乳腺组织中表达率分别为64％（32／50）和22％（11／50）;COX-2在乳腺癌及其周围正常乳腺组织中表达率分别为68％（34／50）和14％（7／50）,差异均有统计学意义（P〈0．05）。TopⅡa的表达仅与乳腺癌组织学分级有关（P〈0．05）,而与患者年龄、肿瘤大小、淋巴结转移和临床分期无关（P〉0．05）;COX-2表达与肿瘤大小、组织学分级、淋巴结转移和临床分期有关（P〈0．05）,而与患者年龄无关（P〉0．05）。结论TopoⅡa和COX-2的检测可作为评价乳腺癌分化程度和侵袭、转移的指标。     

Bcl-2和Bax的表达与乳腺癌组织学分级及预后的关系

目的：探讨bcl-2和bax基因在乳腺癌中的表达与乳腺癌组织学分级及预后的关系。方法：应用SP免疫组化染色方法，检测40例乳腺癌组织中bcl-2、bax的表达情况。结果：组织学I级＋Ⅱ级乳腺癌中bcl-2蛋白阳性表达率与组织学Ⅲ级乳腺癌中bcl-2蛋白阳性表达率有显著差异（P〈0．01），Ⅰ＋Ⅱ级组bax蛋白阳性表达率与Ⅲ级组bax蛋白阳性率表达无显著差异（P〉0．05），Ⅰ级＋Ⅱ级组bcl-2高表达和bax低表达（bcl-2／bax≥1）与Ⅲ级组bcl-2高表达和bax低表达（bcl-2／bax≥1）有显著差异（P〈0．01）。10年以上存活组中bcl-2阳性表达率与10年以下存活组有显著差异（P〈0．01）；10年以上存活组bax阳性表达率与10年以下存活组有显著差异（P〈0．05）；10年以上存活组bcl-2高表达和bax低表达（bcl-2／bax≥1）与10年以下存活组bcl-2高表达和bax低表达（bcl-2／bax≥1）有显著差异（P〈0．05）。结论：bcl-2和bax比值与乳腺癌组织学分级、预后关系密切，bcl-2高表达和bax低表达的乳腺癌患者组织学分级好，预后好。     

组蛋白酶D和c-erbB-2在乳腺癌中的表达及其与预后的关系

目的探讨乳腺癌组织中c-erbB-2和组织蛋白酶D（cath—D）的表达水平与临床病理及预后的关系。方法选取128例乳腺癌患者,采用免疫组化法检测c—erbB-2和cath—D蛋白的表达水平。并与患者的临床病理指标和预后做关联分析。结果c-erbB-2阳性率为36．5％,cath-D阳性表达率为40．9％。cath—D的表达水平与患者肿块直径大小显著相关,肿瘤直径〉5cm者cath—D的阳性率显著高于〈2cm者（x^2=21．0,P〈0．0001）;cath-D阴性的68例中,24例（35．29％）有淋巴结转移,cath-D阳性者淋巴结转移率（63．83％）明显高于cath-D阴性者（P〈O．0001）。c—erbB-2表达比不表达患者预后差（P=0．01）。结论c-erbB-2阳性表达和cath-D阳性表达者,恶性程度高,易转移、预后差。     

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.     

p57kip2 、Cyclin E 在脑胶质瘤中的表达及临床意义

 目的 探讨p57^kip2皿蛋白、Cyclin E蛋白在人脑胶质瘤表达情况及其临床意义。方法 采用免疫组织化学SP法检测p57 ^kip2、Cyclin E在46例胶质瘤和10例正常脑组织中的表达。结果 在46例胶质瘤中，p57 ^kip2蛋白阳性率为34．8％(16／46)，显著低于正常脑组织(70％)(P<0．05)。低度恶性(Ⅰ～Ⅱ)、高度恶性(Ⅲ～Ⅳ级)及两年生存时间组别间差异有显著性(P<0．01)。Cyclin E蛋白阳性率为58．6％(27／46)，显著高于正常脑组织(20％)(P<0．05)。脑胶质瘤不同恶性程度及两年生存时间组别间差异有显著性(P<0．05)。p57 ^kip2蛋白的表达与Cyclin E蛋白的表达密切相关(rn=-0．359)。结论 p57 ^kip2蛋白和Cyclin E蛋白在脑胶质瘤的发生、发展中起重要作用。且与肿瘤的分化程度、患者预后密切相关。     

C-erbB-2 expression does not predict response to docetaxel or sequential methotrexate and 5-fluorouracil in advanced breast cancer

Breast cancer patients with c-erbB-2-positive tumours seem to benefit from anthracycline-based adjuvant chemotherapy. The predictive value of c-erbB-2 for taxane sensitivity is not yet clear. The purpose of this study was to assess whether c-erbB-2 expression is associated with clinical sensitivity to docetaxel (T) or sequential methotrexate and 5-fluorouracil (MF). A total of 283 patients with metastatic breast cancer were initially enrolled in a randomised multicentre trial comparing docetaxel with sequential MF in advanced breast cancer. Paraffin-embedded blocks of the primary tumour were available for 131 patients (46%). c-erbB-2 status was determined by immunohistochemistry using a polyclonal antibody to the c-erbB-2 protein. C-erbB-2 expression was scored in a semi-quantitative fashion using a 0 to 3+ scale. Staining scores 2+ or greater were considered positive. Response evaluation was performed according to World Health Organization (WHO) recommendations. Overall 54 (42%) patients had c-erbB-2-positive tumours. There was no association between treatment outcome and c-erbB-2 overexpression. The overall response rates (RR) (n=128) among c-erbB-2-negative and -positive patients were 35 and 44%, respectively (P=0.359). In the MF arm (n=62), the RR was somewhat higher in the c-erbB-2 overexpressors (33% versus 18%, P=0.18). In the docetaxel arm the RRs were very similar, regardless of the c-erbB-2 expression (53% versus 53%). While several studies have suggested a prognostic and putative predictive significance of c-erbB-2 overexpression in early breast cancer, the significance of c-erbB-2 expression as a predictive factor for response to various cytotoxic treatments in advanced breast cancer is still controversial. In this study, c-erbB-2 expression could not predict response to either MF or T. Thus, tumours over-expressing c-erbB-2 are not uniformly more sensitive to taxanes and c-erbB-2 expression cannot yet be applied clinically as a predictive factor for response in advanced breast cancer.     

Reduced nuclear expression of transcription factor AP-2 associates with aggressive breast cancer.

PURPOSE: We proposed to investigate the expression and prognostic significance of activator protein 2 (AP-2) in breast cancer. EXPERIMENTAL DESIGN: AP-2 was immunohistochemically analyzed in a prospective, consecutive series of 420 breast cancer patients diagnosed and treated between 1990 and 1995 at Kuopio University Hospital, Kuopio, Finland. AP-2 expression was further compared with clinicopathological parameters and patients' survival. RESULTS: Nuclear AP-2 expression was lower in carcinomas compared with normal ductal breast epithelium (P < 0.001). Nuclear expression was more often seen in lobular than in ductal or other carcinomas (P = 0.048). Cytoplasmic staining was present in 47% of the carcinomas. Low nuclear AP-2 expression level in carcinomas was associated with advanced stage (P = 0.002), axillary lymph node positivity (P = 0.012), poor differentiation (P = 0.001), and recurrences (P = 0.003). In univariate survival analyses, low nuclear AP-2 expression (P = 0.0028), advanced stage (P < 0.0001), lymph node metastases (P < 0.0001), and poor differentiation (P = 0.0498) predicted shorter recurrence-free survival (RFS). Low nuclear AP-2 staining and/or shift to cytoplasmic expression predicted shorter RFS (P = 0.0050) and breast cancer-related survival (BCRS; P = 0.0314) in univariate analyses. Cytoplasmic expression alone did not have prognostic value. In multivariate analysis, low nuclear AP-2 expression (P = 0.0292) and advanced stage (P = 0.0001) were independent predictors of shorter RFS; and stage (P < 0.0001) and ER-status (P = 0.0321) independently predicted BCRS. In the lymph-node positive patients, RFS was independently predicted by stage (P = 0.0110) and nuclear AP-2 status (P = 0.0151). CONCLUSIONS: AP-2 seems to have a protective role in breast cancer. Low nuclear AP-2 expression was associated with disease progression and increased metastatic capability of the tumor. In addition, reduced nuclear AP-2 expression independently predicted elevated risk of recurrent disease in breast cancer.     

C-erbB-2 overexpression and survival in early onset breast cancer

Young breast cancer patients have a decreased survival rate and it has been demonstrated that young age is an independent predictor of adverse prognosis. Overexpression of c-erbB-2 protein (also known as HER-2/neu) has been shown to be a prognostic indicator in breast cancer in general and especially among patients with axillary nodal metastases. The present study was initiated to determine the prognostic significance of c-erbB-2 protein overexpression in early onset breast cancer.A population consisting of 110 young breast cancer patients, 36-year-old at diagnosis, was analyzed with immunohistochemical staining for c-erbB-2 protein.Thirty patients (27%) were found to overexpress the c-erbB-2 protein. C-erbB-2 positivity was significantly associated with poor survival when all patients were included in the analysis (P=0.002) and for patients with axillary nodal metastases (P=0.0007). No such association was found for node-negative patients. Furthermore, the difference in prognosis in relation to c-erbB-2 among node-positive patients was maintained, when these were stratified in groups treated or not treated with adjuvant chemotherapy.The study indicates that overexpression of c-erbB-2 protein is a strong prognostic factor in young breast cancer patients with axillary nodal metastases. Moreover, the adverse prognosis associated with c-erbB-2 overexpression in node-positive patients was observed whether or not the patients had received adjuvant chemotherapy.