乳腺癌组织CD15与PCNA表达及其临床意义的研究

目的:通过检测CD15抗原及PC-NA在乳腺癌及乳腺增生症中的表达,探讨CD15抗原及增殖细胞核抗原(PCNA)在乳腺癌鉴别诊断中的价值。方法:采用免疫组织化学SP法检测CD15抗原和PCNA在51例乳腺癌及67例乳腺增生症组织中的表达。结果:CD15抗原在51例乳腺癌组织及67例乳腺增生组织中的阳性表达率分别为78.4%(40/51)和44.8%(30/67),PCNA的阳性表达率分别为88.2%(45/51)和68.7%(46/67),这2个指标表达在乳腺癌与乳腺增生之间差异有统计学意义(P=0.000;P=0.012)。CD15抗原及PCNA阳性表达率与乳腺癌患者腋淋巴结状况及组织学分级有显著相关性(P=0.000),而与患者绝经状况(P=0.554;P=0.288)及TNM分期(P=0.081;P=0.055)无显著相关性。在乳腺癌组织中CD15表达与PCNA表达呈正相关(r=0.479,P=0.000)。结论:CD15抗原和PCNA表达与乳腺癌的发生发展有关。联合检测CD15抗原和PCNA可能对乳腺癌的鉴别诊断及早期诊断具有重要参考价值。CD15抗原和PCNA对判断乳腺癌的恶性程度、预测生物学行为和预后有参考价值。     

人乳头状瘤病毒16和18型感染与乳腺增生症和乳腺癌的关系

目的：探讨人乳头状瘤病毒（human papillomavirus HPV）16、18型感染与乳腺增生症、乳腺癌的关系。方法：采用原位杂交法检测HPV16、HPV18在正常乳腺组织、乳腺增生组织和乳腺癌中的表达。结果：HPV16在乳腺癌、乳腺增生症及正常乳腺组织各60例中的感染率分别为51．67％（31／60）、31．67％（19／60）和11．67％（7／60），差异有统计学意义，P〈0．05；HPV18感染率分别为56．67％（34／60）、35．00％（21／60）和15．00％（9／60），差异有统计学意义，P〈0．05；HPV16和18在乳腺癌、乳腺增生症及正常乳腺组织中的共感染率分别为48．33％（29／60）、15．00％（9／60）和6．67％（4／60），其中乳腺增生症与正常乳腺组织共感染率差异无统计学意义，而与乳腺癌差异有统计学意义，P〈0．01。结论：本组乳腺癌和乳腺增生症组织中HPV16和HPV18感染率明显高于正常乳腺组织中的感染率；HPV16和HPV18感染与乳腺增生、乳腺癌的关系有待进一步探讨。     

Ki67、增殖细胞核抗原在不同分子分型乳腺癌组织中的表达及意义

目的探讨Ki67、增殖细胞核抗原（PCNA）在不同分子类型乳腺癌组织中的表达及临床意义。方法采用免疫组化法检测251例乳腺癌组织中Ki67、PCNA的表达情况,采用kruskal—wallis秩和检验分析Ki67、PCNA在不同分子类型乳腺癌组织中的表达差异;采用Spearman相关分析法,分析不同分子类型中Ki67与PCNA表达的相关性及其分别与原发肿瘤直径、腋窝淋巴结转移及病理组织学分级的相关性;采用生存分析法,分析Ki67、PCNA对乳腺癌预后的意义。结果Luminal型、HER-2型及三阴性乳腺癌组织中Ki67、PCNA表达强度差异均无统计学意义（X^2=3．722,P=0．155;）（X^2=5．135,P=0．077）。Ki67与PCNA总体呈正相关（r1=0．348,P=0．000）,在Luminal型中呈正相关（r3=0．467,P=0．000）,而在HER-2型、三阴性乳腺癌中无相关性（P〉0．05）。Ki67表达强度与原发肿瘤直径、腋窝淋巴结转移及组织学分级在Luminal型乳腺癌呈正相关性（r1=0．180,P：0．017;rs=0．236,P=0．002;0=0．156,P=0．039）,而在HER-2型及三阴性乳腺癌中无相关性（P〉0．05）。PCNA表达强度与Luminal型乳腺癌的腋窝淋巴结转移呈正相关性（r1=0．166,P=0．028）,与HER-2型乳腺癌的原发肿瘤直径呈负相关性（r1=-0．342,P=0．020）,与其他病理因素均无相关性（P〉0．05）。单因素生存分析显示腋窝淋巴结转移、组织学分级对乳腺癌患者无瘤生存有影响（HR=4．431,95％CI：1．787～10．984;HR=2．492,95％C,：1．032～6．018）,亚组分析显示腋窝淋巴结、PCNA对Luminal型乳腺癌患者无瘤生存有影响（HR=3．930,95％C1：1．343～11．501;HR=2．401,95％C1：1．044—5．524）。多因素COX回归分析显示腋窝淋巴结转移是总体和Luminal型乳腺癌患者预后的独立影响因素（HR=3．780,95％CI：1．461—9．775;HR=3．403,95％CI：1．150～10．075）。结论Ki67和PCNA对评估Luminal型乳腺癌预后有一定指导意义,而对HER-2型和三阴性乳腺癌预后无明显影响。     

乳腺癌组织中E-cadherin和CD44V6及uPA的表达及意义

目的：探讨浸润性乳腺癌组织中细胞黏附分子E—cadherin、CD44V6和基质分解酶uPA的表达及意义。方法：SABC法检测86例乳腺癌和10例正常乳腺组织中E—cadherin、CD44V6与uPA的表达，探讨三者之间的相互关系。结果：E—cadherin在正常对照组均为强阳性表达，在乳腺癌组织中淋巴结转移组和无淋巴结转移组的阳性率分别为27．4％（17／62）和83．3％（20／24），两组比较差异有统计学意义，X^2=22．067，P=0．000；CD44V6与uPA在正常对照组均呈阴性表达，在乳腺癌淋巴结转移组的阳性率分别为90．3％（56／62）和77．4％（48／62）；无淋巴结转移组的阳性率分别为62．5％（15／24）和16．7％（4／24），两者的表达差异均有统计学意义（X^2=7．470、26．715，P=0．006、0．000）。相关分析结果显示，乳腺癌组织中E-cadherin的表达与CD44V6及uPA的表达均亦呈负相关。结论：E-cadherin和CD44V6及uPA的表达与乳腺癌的浸润转移密切相关，同步检测其在乳腺癌组织中的表达并综合分析三者之间的关系对评价乳腺癌细胞的侵袭转移能力及预后判断具有一定价值。     

乳腺癌组织中CD15与PCNA的表达及相互关系

目的；研究黏附分子CD15及增殖细胞核抗原（PCNA）在乳腺癌表达的临床病理意义及其相互关系。方法：应用免疫组化S－P法检测了64例乳腺癌CD15，PCNA的表达.结果：CD15在肿瘤细胞膜表达亦可伴有浆染色，在乳腺癌中阳性率为54．69％（35／64）；PCNA在细胞核表达，过表达率为51．56％（33／64）；CD15与PCNA的表达与乳腺癌组织学分级高，淋巴结有转移呈正相关；并且两者相互呈正相关。结论；CAD15，PCNA的表达可作为反映乳腺癌低分化及易转移的有用指标。     

乳腺肿瘤组织中端粒酶的表达及其对诊治的意义

背景与目的：研究表明,端粒酶的活化可使细胞转化为癌细胞。本研究拟分析端粒酶在乳腺良性和恶性组织中的表达及其对乳腺癌早期诊断的价值。方法：应用PCR－ELISA方法检测178例乳腺癌、乳腺纤维瘤等患者术后组织中端粒酶的表达。结果：端粒酶阳性表达率在原发性乳腺癌组织为86．72％（111／128）;乳腺癌癌前病变组织为46．67％（7／15）;乳腺纤维瘤组织为26．66％（4／15）;乳腺非癌组织、囊性增生组织全阴性。乳腺癌在不同的临床分期中,端粒酶阳性表达率为临床I期63．16％,Ⅱ期85．96％,Ⅲ期为965％,Ⅳ期为100％。原发性乳腺癌伴腋窝淋巴结阳性者端粒酶阳性表达率为95．83％（69／72）,腋窝淋巴结阴性者端粒酶阳性表达率75％（42／56）。结论：端粒酶的表达与乳腺癌的临床分期（P＜0．005）,腋淋巴结转移密切相关（P＜0．01）。特别是它在乳腺癌癌前病变中有表达。端粒酶的检测对乳腺癌的早期诊断具有重要价值。     

乳腺癌组织中缺氧诱导因子-1α和葡萄糖转运蛋白1表达及其意义

目的探讨乳腺癌组织中缺氧诱导因子-1α（HIF-1α）和葡萄糖转运蛋白1（Glut1）表达的关联性及其与细胞增生活性和临床病理因素的关系。方法采用免疫组织化学方法检测HIF-1α、Glut1、增生细胞核抗原（PCNA）在80例乳腺癌组织、20例乳腺纤维腺瘤及20例乳腺增生组织中的表达水平并比较它们之间的相关性。结果HIF-1α和Glut1在乳腺纤维腺瘤、乳腺增生组织中不表达；HIF-1α在乳腺导管内原位癌中阳性率55．0％（11／20），浸润性乳腺癌中85．0％（51／60）；乳腺癌中Glut1阳性率58．8％（47／80）；乳腺癌中PCNA阳性率75％（60／80），其中原位癌65％（13／20），浸润癌78．3％（47／60）。乳腺癌中HIF-1α表达与Glut1呈显著正相关（r=0．653，P〈0．01）；HIF-1α表达与PCNA呈显著正相关（r=0．693，P〈0．01）；Glut1与PCNA呈显著正性相关（r=0．742，P〈0．01）。HIF-1α和Glut1在淋巴结、雌激素受体状态及组织学分级中表达差异有统计学意义；Glut1在肿瘤大小及孕激素受体状态表达差异也有统计学意义。结论HIF-1α和Glut1蛋白的过表达共同参与了乳腺癌的发生、发展，与乳腺癌细胞增生活性密切相关，有望成为乳腺癌治疗的新靶点。     

骨桥蛋白在浸润性乳腺癌组织中的表达及其与微血管密度的关系

目的探讨乳腺癌组织中不同骨桥蛋白（OPN）的表达水平及其与微血管密度的关系。方法采用免疫组织化学Envision法检测89例乳腺浸润性导管癌组织OPN和CD34的表达情况,分析其表达与病理特征的关系。定性资料分析采用x2检验,定量资料分析采用t检验。结果在89例乳腺浸润性导管癌中,OPN阳性表达率为57．30％（51／89）。组织学分级Ⅰ、Ⅱ、Ⅲ级浸润性导管癌OPN阳性表达率分别为27．27％（6／22）、66．67％（24／36）、67．74％（21／31）,三者间差异有统计学意义（x2=10．780,P=0．005）;有、无淋巴结转移者OPN阳性表达率分别为74．47％（35／47）和38．10％（16／42）,伴有淋巴结转移者OPN阳性表达率明显高于不伴转移者（x2=11．993,P=0．001）。乳腺癌组织OPN表达阴性、阳性组的肿瘤微血管密度（MVD）分别为（68．42±23．45）条／每高倍视野和（94．96±31．03）条／每高倍视野,二者间差异有统计学意义（t=4．413,P=0．000）。结论OPN在乳腺癌组织中的高表达与肿瘤血管的生成和肿瘤的浸润及转移有一定关系,针对OPN的进一步研究可能为临床治疗乳腺癌转移提供新的方法。     

金属蛋白酶组织抑制因子1在乳腺癌组织中的表达及其与多种生物学指标的关系

目的研究乳腺癌组织中金属蛋白酶组织抑制因子1（TIMP-1）的表达及其与增殖细胞核抗原ki67、P53癌基因（P53gene）、人表皮生长因子受体-2（HER-2）表达的关系。方法应用免疫组织化学方法（SP法）检测104例乳腺癌和33例癌旁乳腺组织TIMP-1的表达情况以及乳腺癌组织Ki67、P53、HER-2的表达情况。非等级计数资料比较采用）χ2检验,等级计数资料比较采用Mann—WhitneyU或Kruskal—WallisH非参数秩和检验。两指标间的相关性采用Spearman相关分析。结果TIMP—1在乳腺癌组织中的阳性表达率为69．23％（72／104）,在癌旁乳腺组织中的阳性表达率为15．15％（5／33）,二者间差异有统计学意义（χ2=29．76,P=0．00）。TIMP-1表达与年龄、月经状态、手术方式、临床分期、肿瘤病理类型等因素无关（P〉0．05）,与肿瘤直径、组织学分级、淋巴结转移有关（P〈0．01）。TIMP-1阳性表达与Ki67表达呈正相关（r=0．28,P〈0．01）,与P53表达呈负相关（r=-0．42,P〈0．01）,与HER-2表达不相关（r=-0．01,P〉0．05）。结论TIMP-1在乳腺癌组织中表达增高,且与乳腺癌侵袭过程关系密切;TIMP-1与多种生物学指标联合检测能更准确地预测预后、指导治疗。     

265例乳腺癌手术前后血清CA15-3和CEA检测分析

[目的]探讨乳腺癌手术前后血清糖类抗原15．3（CA15—3）和癌胚抗原（CEA）测定的临床意义。[方法]取265例乳腺癌病例外周静脉血，采用电化学发光免疫分析fECLIA）检测术前及术后CA15—3、CEA水平。[结果]术前已发生转移者23例，CA15—3增高18例，CEA增高10例，阳性率分别为78-3％、43．5％；术后无复发转移组201例，CA15—3增高2例（0．99％）、复发转移组41例，CA15-3增高33例，CEA增高27例，阳性率分别为80．5％和65．9％。[结论]血清CA15-3和CEA的动态检测可作为乳腺癌术后随访的监测指标，CA15-3水平的变化有助于预测肿瘤转移及其治疗效果的判定。     

CA15-3和CEA联合检测在乳腺癌术后疗效评价中的价值

目的　观察CA15 3和CEA联合检测在乳腺癌术后随访中的价值。方法　空腹取静脉血分别采用免疫放射分析法 (IRMA)和放射免疫法 (RIA)测定CA15 3和CEA。结果　①乳腺癌术后无复发转移12 7例 ,其中CA15 3增高 3例、CEA增高 2例 ,阳性率分别为 2 4 %、1 6 %。复发转移者 18例 ,其中CA15 3增高 15例、CEA增高 8例 ,其敏感度分别为 83 3%、4 4 4 % ,特异度分别为 97 6 %、98 4 %。CA15 3和CEA两者均异常在无复发转移组为 0 ,复发转移组 6例 ,其敏感度为 33 3% ,特异度为 10 0 %。联检两者之一阳性 16例 ,其敏感度为 88 9% ,特异度为 96 1%。经 χ2 检验 ,与单独检测CA15 3比较无显著性差异 (P >0 .0 5 )。②复发或转移乳腺癌患者CA15 3和CEA水平显著高于无复发或转移乳腺癌患者 (P <0 .0 1)。结论　CA15 3和CEA的检测可作为乳腺癌术后随访的重要指标 ,单独检测CA15 3和 或联合CEA对预测复发转移具有重要意义。     

The diagnostic and prognostic utility of prostate-specific antigen for diseases of the breast

Although prostate-specific antigen (PSA) is the most valuable tumor marker for the diagnosis and management of prostate carcinoma, it is widely accepted that PSA is not prostate specific. Numerous studies have shown that PSA is present in some female hormonally regulated tissues, principally the breast and its secretions. In this review, we summarize the findings of PSA in the breast, and focus on its potential for clinical applications in breast disease. PSA is produced by the majority of breast tumors and is a favorable indicator of prognosis in breast cancer. Low levels of PSA are released into the female circulation, and while the level of serum PSA is elevated in both benign and malignant breast disease, the molecular form of circulating PSA differs between women with and without breast cancer. These findings indicate that PSA may have potential diagnostic utility in breast cancer. PSA may also have a clinical application in benign breast disease, as both the level and molecular form of PSA differ between Type I and II breast cysts. High levels of PSA have been reported in nipple aspirate fluid (NAF) and recent studies have shown that the concentration of PSA in NAF is inversely related to breast cancer risk, indicating that NAF PSA may represent a clinical tool for breast cancer risk assessment. Thus, PSA represents a marker with numerous potential clinical applications as a diagnostic and/or prognostic tool in breast disease.     

Detection and purification of a novel 72 kDa glycoprotein male breast tumor associated antigen

A male breast tumor associated antigen (MBTAA) was purified and partially characterized from human male breast tumor. Three protein peaks were obtained by DEAE-cellulose column chromatography of a crude extract of human male breast tumor tissues. Circulating antibodies against one of these peaks, MF1, which contained MBTAA, were observed in male breast cancer patients but not in normal male or male patients with carcinoma of other organs (stomach, colon, lung). The MBTAA was partially purified from MF1 by subjecting the fraction to SDS-PAGE and eluting the protein from band 3 (MB-3) and by subjecting MF1 to size exclusion-high performance liquid chromatography (SE-HPLC). The MBTAA was characterized as a glycoprotein with MW of approximately 72 kDa. It showed no immunological relatedness with TAG-72, a tumor associated antigen expressed in breast epithelial cells. A 72 kDa protein, immunologically related to MBTAA, was detected and partially purified from female breast tumor. The female breast cancer patients did not have circulating antibodies against this 72 kDa protein or MBTAA. Presence of 72 kDa glycoprotein MBTAA in MF1 and specificity of the anti-MBTAA antibodies in the sera of male breast cancer patients were further confirmed by Western blot analysis. Absence of anti-MBTAA antibodies in healthy men and in patients with other cancers suggested that expression of MBTAA may be malignancy-associated and is highly overexpressed in male breast cancer.     

Use of autoantibodies in breast cancer screening and diagnosis

Breast cancer is the most common cancer among women and accounts for 6% of all cancer deaths. Current screening modalities for breast cancer diagnosis include mammography, digital mammography and magnetic resonance imaging; however, there is still an urgent need to develop an alternative modality of screening for earlier diagnosis. Autoantibodies to tumor-associated autoantigens can be elicited in breast cancer patients. Tumor-associated antigens vary between cancers and can be the result of a number of different events, including mutation, overexpression or altered expression patterns. The inherent amplification of signals provided by the host’s own immune system to low levels of tumor-associated antigens in early disease provides a potential route to the early diagnosis of cancer. In addition, autoantibody responses in breast cancer have been correlated with patient survival and their response to treatment.     

Normal epithelial antigens recognized by GB3 and GB5 are diminished in intraductal and lost in infiltrating human breast carcinomas

GB3 and GB5 are mouse monoclonal antibodies raised against human amnion. GB3 detects the epidermal basement membrane, and GB5 reacts with the junctional substances between the epithelial cells. These two antibodies were studied on breast tissues by indirect immunofluorescence. All (n = 8) of the normal mammary glandular basement membranes and epithelia reacted strongly with GB3 and GB5. In the intraductal carcinomas (n = 10), although nine out of ten tissues were reactive, their reactivities were greatly reduced. More strikingly, in the infiltrating carcinomas (n = 15), none of the tumor specimens were recognized by GB3 and only one out of fifteen biopsies was moderately reactive with GB5, indicating that the syntheses of the antigens of GB3 and GB5 were discontinued in the metastatic breast adenocarcinomas. These data suggest that these antigens may contribute to the interaction of the epithelium with the extracellular matrix and the intercellular binding between the epithelial cells; the loss of these antigens may facilitate the wide dissemination of tumor cells.     

Adenocarcinoma-associated antigen: Enhancement of tumor growth with serum from animals bearing adenocarcinoma

Why do tumors continue to grow in the presence of cell-mediated immune reactions? When inoculated subcutaneously, 10⁵ viable spontaneous mammary adenocarcinoma cells produced solid tumors that progressively proliferated and eventually kilted all the recipient mice. During the first 10 days after inoculation, the mice developed antibody titers, and the serum acquired toxic activity against the tumor cells. As the tumor gained in size these two activities ceased. Serum of normal mice had no effect on the tumor; the serum of mice immunized with an adenocarcinoma-associated antigen (a glycoprotein) inhibited growth, but that of mice with progressive tumors enhanced proliferation of the tumors.     

A comparison of tumor-related antigens in male and female breast cancer

Summary A retrospective analysis was undertaken in which 15 female and 15 male breast cancers were matched by age, stage, estrogen receptor status, and histologic type. Our protocol compares male and female breast cancers for reactivity with antibodies against tumor-associated antigens known to be present on female breast cancer cells. Formalin-fixed sections of each primary tumor were reacted in the ABC immunoperoxidase assay against antibodies B72.3 and DF.3 and an antibody to theras p21 antigen. Reactivity to B72.3 and DF.3 was similar. However, the ras p21 antigen was expressed to a significantly greater extent in female breast cancers (p = .0008). Thus, although there are similarities in antigenic phenotype of male and female breast cancers, some female breast cancers may have a different pathogenesis as demonstrated by increased amounts of a specific oncogene product.     

Quantitative analysis of mutant p53 protein in breast tumor cytosols and study of its association with other biochemical prognostic indicators in breast cancer

Breast tumors are thought to originate, grow, and metastasize in an environment which includes steroid hormone receptors, their cognate steroid ligands, and many gene products which are regulated by steroid hormone receptor-ligand complexes. In this paper we describe highly sensitive and quantitative immunofluorometric procedures for measuring three proteins that are candidate prognostic indicators in breast cancer, namely, the p53 tumor suppressor gene product, carcinoembryonic antigen (CEA), and prostate specific antigen (PSA). These proteins were quantified in over 950 cytosolic tumor extracts along with estrogen and progesterone receptors (ER, PR). Association analysis between all five biochemical parameters revealed strong negative associations between p53 and receptors and strong positive associations between CEA and receptors. Negative associations between p53 and CEA and between CEA and PSA were also found. These associations, not quantitatively studied in previous reports, are related to each other using a hypothetical model. The observed associations may further contribute to the understanding of the biology of breast tumors.