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．     

MUC1在不同免疫表型乳腺癌组织中的强阳性表达及其与预后的关系

目的探讨黏蛋白1(mucin1,MUC1)强阳性表达在不同免疫表型乳腺癌中对指导预后及个体化治疗的意义。方法采用免疫组织化学法检测335例乳腺癌组织中ER、PR和HER2的表达,将乳腺癌分为四个免疫表型,采用免疫组织化学法测定各免疫表型中MUC1的阳性及强阳性表达情况,并对其与不同免疫表型乳腺癌预后的关系进行统计分析。结果 335例乳腺癌患者中MUC1强阳性表达率为46.3%,MUC1强阳性表达患者5年总生存率低于非强阳性表达者,两者之间差异存在统计学意义(P<0.05)。335例乳腺癌中ER+/PR+、HER2-型130例,ER+/PR+、HER2+型64例,ER-、PR-、HER2+型67例,ER-、PR-、HER2-型74例;MUC1强阳性表达率分别为59.2%、56.3%、32.8%和27.0%,MUC1强阳性表达与乳腺癌免疫表型相关(P<0.01)。预后分组分析表明ER+/PR+、HER2-型,ER-、PR-、HER2+型乳腺癌患者中,MUC1强阳性表达患者5年总生存率低于非强阳性表达者,差异有统计学意义(P<0.05)。结论 MUC1强阳性表达与乳腺癌免疫表型相关,在不同免疫表型乳腺癌预后中的作用也有所不同,在ER+/PR+、HER2-型及ER-、PR-、HER2+型乳腺癌中MUC1强阳性表达提示预后较差。     

ER阳性乳腺癌中MUC1的强阳性表达及其与预后的关系

背景与目的:黏蛋白1(mucin 1,MUC1)主要作为血清学分子标记应用于乳腺癌患者术后肿瘤复发转移的监测,但其在乳腺癌患者术后早期检测对预后的价值尚不明确.本研究旨在通过检测乳腺癌组织中MUC1的强阳性表达,分析其与ER表达以及预后的关系,以探讨MUC1强阳性表达在乳腺癌术后早期检测对预后的作用.方法:采用免疫组织化学法检测134例乳腺癌组织中MUC1的强阳性表达情况,并分析其与ER表达以及预后的关系.结果:本组乳腺癌组织中MUC1强阳性表达率为47.0%,乳腺癌组织中MUC1强阳性表达与ER阳性表达存在着显著的正相关关系(x2=10.09,P＜0.01,r=0.27).在ER阴性乳腺癌患者中尚不能认为MUC1强阳性表达与预后相关(P=0.26);经单因素和多因素分析,在ER阳性并接受他莫昔芬治疗的乳腺癌患者中,MUC1强阳性表达、Her-2强阳性表达和淋巴结转移状态均是独立的预后因子(P＜0.05).同时,多因素分析表明Her-2强阳性表达的优势比最大(OR=12.41),淋巴结转移状态次之,MUC1强阳性表达最小.结论:在乳腺癌组织中MUC1强阳性表达与ER表达正相关,在ER阳性并接受他莫昔芬治疗的乳腺癌患者中MUC1强阳性表达具有独立的预后价值.     

乳腺癌HER-2基因的表达及其临床意义

目的分析HER-2表达的临床意义及病理特征,观察HER-2表达对乳腺癌预后的影响。方法用LSAB免疫组织化学法检测267例乳腺癌石蜡标本HER2癌基因的表达,结合临床表现、病理学指标及随访资料,进一步分析其对乳腺癌预后的影响。结果HER2在年轻患者及ER、PR阴性者表达率高,分别为78.0%、63.0%和60.5%。HER-2阳性表达与病理类型无关(P=0.60)。有淋巴结转移组HER-2阳性表达率明显高于无淋巴结转移组,差异有显著性(P<0.001)。HER-2阳性的乳腺癌患者生存时间明显短于阴性者(P<0.001)。结论癌基因HER2的过度表达与乳腺癌腋窝淋巴结有转移、雌、孕激素受体缺乏及预后差有关。HER2基因的表达是乳腺癌中腋淋巴结状况之外的又一个独立预后因素。该基因表达的检测作为乳腺癌常规病理检查,可用于判断乳腺癌的预后及拟定术后治疗方案。     

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。     

转录因子粒状头样2 在乳腺癌组织中的表达及其与患者临床病理特征和预后的关系

目的：探讨转录因子粒状头样2(GRHL2)在乳腺癌组织中的表达及其与患者临床病理特征和预后的关系,为乳腺的临床治疗寻找新的靶点。方法：选取2010 年1 月至2017 年1 月在新乡市中心医院普外二科诊疗并经病理确认的初发乳腺癌患者88 例的癌组织及相应的癌旁组织。免疫组织化学染色法检测GRHL2 在乳腺癌组织及相应的癌旁组织中的表达,并分析GRHL2 的表达水平与患者临床病理特征的关系;通过分析TCGA乳腺癌临床数据,探究GRHL2 的表达与乳腺癌患者预后的关系。结果：乳腺癌组织中GRHL2 的表达率（75.00%）明显高于癌旁组织（36.36%）（P<0.01）。TCGA数据库中114 例正常乳腺组织以及1 097 例原发性乳腺癌组织中GRHL2 的表达结果显示,原发性乳腺癌组织中GRHL2 的表达高于正常乳腺组织,差异有统计学意义（P<0.01）。GRHL2 的表达与乳腺癌TNM分期、组织学分级、HER2 表达、淋巴结转移状态等相关（均P<0.05）;通过分析TCGA数据库中1 979 例低表达GRHL2 乳腺癌患者与1 972 例高表达GRHL2 乳腺癌患者无复发生存期（RFS）结果显示,高表达GRHL2 的乳腺癌患者RFS患者显著缩短（HR=1.24,95%CI:1.11～1.38,P<0.01）;GRHL2表达差异对TNBC乳腺癌患者的RFS无明显影响（HR=1.30,95%CI: 0.89～1.88,P=0.170）;GRHL2 的表达差异对ER+乳腺癌患者的RFS 无明显影响（HR=1.17,95%CI:0.76～1.78,P=0.470）;但是高表达GRHL2 的HER2+乳腺癌患者其RFS显著低于低表达GRHL2 的HER2+乳腺癌患者（HR=1.72,95%CI:1.11～2.68,P=0.015）。结论：GRHL2 在乳腺癌组织中表达升高,并与HER2 表达、组织学分级、TNM分期、淋巴结转移密切相关,在乳腺癌发生发展过程中发挥重要作用,提示不良预后。     

AKAP12在HER2阳性乳腺癌中表达及其临床意义

目的 探讨人表皮生长因子受体2（HER2）阳性乳腺癌中A激酶锚定蛋白12（AKAP12）表达及与HER2阳性乳腺癌患者临床病理特征的关系和临床意义。方法 采用UALCAN数据库分析乳腺癌组织和正常组织中AKAP12 mRNA表达情况；免疫组织化学法检测120例HER2阳性乳腺癌组织、癌旁组织及8例转移灶组织中AKAP12蛋白表达，分析癌组织中AKAP12蛋白表达与临床病理因素关系；Bc-GenExMinerv4.4用于分析AKAP12 mRNA表达与HER2阳性乳腺癌预后的关系，GraphPad Prism 7.0分析AKAP12蛋白表达与HER2阳性乳腺癌预后的关系。结果 乳腺癌组织中AKAP12显著低于癌旁组织（P<0.05），HER2阳性乳腺癌转移灶中AKAP12蛋白显著低于原发灶（P<0.05）。AKAP12蛋白与肿瘤大小、TNM分期负相关（P<0.05）。生存分析发现AKAP12 mRNA和蛋白低表达患者总生存期较高表达者显著缩短（P<0.05）。单因素及多因素Cox回归分析发现AKAP12蛋白表达、脉管浸润及放射治疗是影响HER2阳性乳腺癌预后的独立风险因素。结论 AKAP12在HER2阳性乳腺癌中的低表达与患者预后差有关。     

ER和PR阴性乳腺癌雄激素受体与HER2表达相关性及其临床意义

目的 激素受体阴性(ER-/PR-)乳腺癌具有明显的肿瘤异质性,临床治疗手段相对有限.本研究探讨激素受体阴性乳腺癌组织中,雄激素受体(androgen receptor,AR)和HER2表达的相关性,及其与临床病理参数和预后的相关性.方法 收集中国人民解放军福州总医院经手术治疗并病理确诊的乳腺癌120例,中位年龄52岁.采用FISH法检测收集的激素受体阴性乳腺癌组织HER2/neu基因状态,分为HER2阳性(HER2过表达组)和HER2阴性(三阴组)两组,每组60例.并采用EliVisionTM plus免疫组化法检测AR、Ki-67、EGFR表达,分析HER2和AR表达与临床病理参数、3年无病生存期(disease free survival,DFS)的相关性.结果 AR在激素受体阴性乳腺癌组织阳性率为61.67％(74/120),HER2过表达组和三阴组分别为73.33％(44/60)和50.00％(30/60).激素受体阴性乳腺癌组织中,AR表达与月经状态、肿瘤大小、组织学分级、EGFR表达及HER2状态相关,均P值＜0.05;在HER2过表达组中,AR表达与月经状态、淋巴结受累、EGFR表达相关,均P值＜0.05;三阴组中,AR表达与肿瘤大小和组织学分级相关,均P值＜0.05.Kaplan-Meier法分析显示,HER2过表达组中AR表达与患者的3年DFS呈正相关,P＜0.05;Cox回归法分析结果示,肿瘤大小、淋巴结受累、EGFR表达、AR表达均与患者的3年DFS有关,P＜0.05.结论 AR可能成为筛选激素受体阴性乳腺癌高危人群和预测其预后的辅助指标之一,可作为激素受体阴性乳腺癌的新治疗靶点,为不同HER2状态乳腺癌治疗提供新思路.     

T1期HER2阳性乳腺癌患者临床特征及抗HER2靶向治疗对预后的影响分析

目的 总结T1期HER2阳性乳腺癌患者的临床病理特征,并分析抗HER2靶向治疗对预后的影响.方法 选取T1期HER2阳性乳腺癌患者50例,总结其临床病理特征,运用统计学方法分析影响患者预后的因素及抗HER2靶向治疗与患者预后关系.结果50例患者中T1a~1b期共13例(26%),T1c期共37例(74%),共4例出现复发转移,无死亡,总随访时间6~36个月,中位随访时间22个月;不同组织学分级、临床分期、脉管是否浸润、腋窝淋巴结是否转移、Ki-67是否为阳性、是否接受抗HER2靶向治疗的T1a~1b期与T1c期患者例数比较,差异有统计学意义(P﹤0.05);与未接受抗HER2靶向治疗患者(无病生存率为89.7%)相比,接受完整抗HER2靶向治疗患者3年内无患者出现复发转移(无病生存率为100.0%),差异有统计学意义(P=0.046);脉管浸润组及腋窝淋巴结转移组中是否接受靶向治疗患者的无病生存率比较,差异有统计学意义(P﹤0.05);Cox多因素分析显示腋窝淋巴结是否转移是影响T1期HER2阳性乳腺癌患者预后的独立因素.结论 T1期HER2阳性乳腺癌患者是否有腋窝淋巴结转移是其预后的独立影响因素,抗HER2靶向治疗对T1期HER2阳性乳腺癌伴随脉管转移或腋窝淋巴结转移患者预后较好.     

乳腺癌患者人表皮生长因子受体2基因扩增状态与临床病理特征的关系

目的探讨乳腺癌患者人表皮生长因子受体2(HER2)基因的扩增状态与患者临床病理特征相关性,并分析乳腺癌患者腋窝淋巴结转移的影响因素。方法收集2016年1月至2019年3月在滕州市中心人民医院病理科做常规病理检查且HER2免疫组织化学(IHC)结果为++的262例乳腺癌患者病理资料,包括年龄、肿瘤长径、组织学分级、病理类型、是否有淋巴结转移、肿瘤数量、肿瘤部位;用IHC法检测石蜡标本p53、Ki-67、雌激素受体(ER)、孕激素受体(PR)的表达结果;用荧光原位杂交(FISH)法检测HER2基因的扩增状态;分析HER2基因扩增是否与上述临床病理特征相关,以及腋窝淋巴结转移是否与上述特征相关。结果262例乳腺癌患者有69例HER2扩增阳性,阳性扩增率为26.3%;HER2基因扩增与Ki-67增殖指数和ER、PR的表达状态相关,差异有统计学意义(χ^2=13.27,P<0.01;χ^2=34.97,P<0.01;χ^2=38.31,P<0.01);与年龄、肿瘤长径等其余临床病理特征均无关(均P>0.05)。262例乳腺癌患者中发生腋窝淋巴结转移106例(40.5%);淋巴结转移与肿瘤长径显著相关(χ^2=29.10,P<0.01),与其余临床病理特征均无相关(均P>0.05)。结论乳腺癌HER2基因扩增状态与Ki-67增殖指数和ER、PR的表达相关,肿瘤大小为影响乳腺癌患者腋窝淋巴结转移的因素,准确判断上述指标能更好地指导乳腺癌患者的治疗和评估预后。     

PD-1/PD-L1抑制剂联合曲妥珠单抗在HER2阳性乳腺癌中的研究进展

乳腺癌中有20%~30%的患者表达HER2基因,HER2阳性乳腺癌预后较差,易发生复发和转移。但HER2的表达为乳腺癌治疗提供了新方向。曲妥珠单抗是抗HER2治疗的经典基础药物,然而其原发继发耐药问题引起了大家的注意,研究发现其不敏感及耐药机制的发生可能与肿瘤细胞表面PD-L1上调相关。因此大量关于PD-1/PD-L1抑制剂联合曲妥珠单抗的研究展开意在提高其敏感度,改善其耐药问题。本文就PD-1/PD-L1抑制剂在HER2阳性乳腺癌的临床前及临床研究作一综述。     

Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non-small cell lung cancer

The HER2 oncogene, which encodes the tyrosine kinase receptor, is commonly overexpressed in several types of cancer. Treatment using a humanized monoclonal antibody bound to HER2 product is becoming standard therapy for advanced breast cancer. Overexpression occurs in approximately 30% of non-small cell lung cancers (NSCLCs) and has been associated with poor prognosis. However, the frequency of a genetic aberration in the HER2 gene in lung cancer and the association between gene amplification and prognosis are poorly defined. To clarify these relationships, we simultaneously analyzed protein overexpression by immunohistochemistry (IHC) and determined the gene copy number by FISH in 50 surgical specimens of NSCLC. A low-grade increase in the copy number (3 to 8 copies) of the HER2 gene was detected in 44% of tumors. Most represented polysomy of chromosome 17. Protein overexpression was observed in 26%. Overexpression was detected in adenocarcinoma more frequently than in squamous cell carcinoma. No significant correlation was observed between copy number increase and overexpression. Neither gene copy number increase nor overexpression correlated with survival. We conclude that the significance of HER2 status in NSCLC is different from that in breast cancer because high-grade amplification occurs rarely.     

A class of genes in the HER2 regulon that is poised for transcription in breast cancer cell lines and expressed in human breast tumors

HER2-positive breast cancer accounts for 25% of all cases and has a poor prognosis. Although progress has been made in understanding signal transduction, little is known of how HER2 achieves gene regulation. We performed whole genome expression analysis on a HER2⁺ and HER2⁻ breast cancer cell lines and compared these results to expression in 812 primary tumors stratified by their HER2 expression level. Chip-on-chip with anti-RNA polymerase II was compared among breast cancer cell lines to identify genes that are potentially activated by HER2. The expression levels of these HER2-dependent POL II binding genes were determined for the 812 HER2+/− breast cancer tissues. Genes differentially expressed between HER2+/− cell lines were generally regulated in the same direction as in breast cancer tissues. We identified genes that had POLII binding in HER2⁺ cell lines, but without significant gene expression. Of 737 such genes “poised” for expression in cell lines, 113 genes were significantly differentially expressed in breast tumors in a HER2-dependent manner. Pathway analysis of these 113 genes revealed that a large group of genes were associated with stem cell and progenitor cell control as indicated by networks centered on NANOG, SOX2, OCT3/4. HER2 directs POL II binding to a large number of genes in breast cancer cells. A “poised” class of genes in HER2⁺ cell lines with POLII binding and low RNA expression but is differentially expressed in primary tumors, strongly suggests a role of the microenvironment and further suggests a role for stem cells proliferation in HER2-regulated breast cancer tissue.     

Associations between the Expression of Mucins (MUC1, MUC2, MUC5AC,and MUC6) and Clinicopathologic Parameters of Human Breast Ductal Carcinomas

Purpose

Mucins are members of the glycoprotein family expressed in benign and malignant epithelial cells. The aim of this study is to evaluate the relationships between the expression of mucins in breast ductal carcinoma and clinicopathologic parameters.

Methods

We constructed tumor microarrays based on 240 cases of invasive ductal carcinoma and 40 cases of ductal carcinoma in situ (DCIS) using formalin fixed, paraffin embedded tissues. We examined the expressions of MUC1, MUC2, MUC5AC, and MUC6 by immunohistochemistry.

Results

MUC1 demonstrated cytoplasmic, membranous, apical, and combinative expressions. Other mucins demonstrated cytoplasmic expression. In invasive ductal carcinoma, MUC1, MUC2, MUC5AC, and MUC6 were expressed in 93.6%, 6.2%, 4.8%, and 12.4% of cases, respectively; these rates were slightly, but not significantly, higher than observed in cases of DCIS. MUC1 expression was associated with estrogen receptor (ER) expression and negative MUC1 expression was associated with triple negativity. MUC6 expression was correlated with higher histologic grade, lymphatic invasion, lymph node metastasis, and HER2 positivity. No associations with any other clinicopathologic parameters were observed.

Conclusion

Most invasive ductal carcinomas of the breast express MUC1, and this expression is associated with ER expression. MUC6 expression is correlated with some clinicopathologic parameters that are indicators of poor prognosis. To evaluate the role of MUC6 as a potential biomarker, further studies are warranted.