簇集蛋白在乳腺浸润性导管癌中的表达及临床意义

 目的　探讨细胞凋亡抑制因子簇集蛋白在乳腺浸润性导管癌组织中的表达及临床意义。方法　应用免疫组织化学SP法检测70例乳腺浸润性导管癌、20例乳腺增生和10例乳腺癌旁组织（距癌组织≥4 cm,组织学结构正常）标本中簇集蛋白的表达情况,并探讨其与乳腺癌各临床病理学参数间的关系。结果　簇集蛋白在乳腺癌旁正常组织、乳腺增生及乳腺浸润性导管癌组织中的阳性表达率分别为0、20.0 %（4／20）及71.4 ％（50／70）,乳腺浸润性导管癌组织中的簇集蛋白表达水平明显高于乳腺增生（χ2＝17.143,P＜0.05）及乳腺癌旁正常组织（χ2＝19.048,P＜0.05）;簇集蛋白在乳腺浸润性导管癌中的表达随着临床分期的增加阳性表达率显著升高（χ2＝4.667,P＜0.05）且与组织学分级（χ2＝5.233,P＜0.05）及淋巴结转移情况（χ2＝4.667,P＜0.05）有关,与患者年龄、肿瘤大小及组织学类型无关（χ2值分别为0.024、0.406、0.091,均P＞0.05）。在乳腺浸润性导管癌组织中簇集蛋白与ER、PR的表达负相关（r值分别为-0.362、-0.290,均P＜0.05）,与C-erbB-2的表达无相关性（r＝0.129,P＞0.05）。结论　簇集蛋白可能通过抑制细胞凋亡在乳腺癌的发生、发展中发挥重要促进作用,可能成为乳腺浸润性导管癌诊断中的标志物,并有望成为乳腺癌治疗的新靶点。     

乳腺癌HOXA4基因甲基化的检测及其临床意义

目的探讨乳腺癌患者HOXA4基因启动子甲基化的情况及其与临床病理特征的相关性。 方法运用NEBNext^? Ultra? RNA Library Prep Kit for Illumina^?进行基因表达芯片测序,运用随机数字表法选择2014年深圳市宝安区妇幼保健院收治的9例乳腺癌患者,分析癌组织与相应癌旁组织异常差异表达的基因。运用Illumina Infinium HD Methylation 450K Assay进行DNA甲基化测序,分析乳腺癌甲基化差异基因。基于肿瘤基因组图谱(The Cancer Genome Atlas,TCGA)数据库信息,分析乳腺癌的差异表达基因和差异甲基化基因。挑选显著高甲基化与低表达的基因,结合生物信息学,确定HOXA4为候选基因。运用随机数字表法收集2014—2017年深圳市宝安区妇幼保健院收治的另外86例乳腺癌患者,采用焦磷酸测序法和RT-PCR,检测乳腺癌组织及其癌旁乳腺组织中HOXA4基因甲基化率和mRNA表达,用Fisher确切概率法分析甲基化率与患者临床病理特征的关系。用Cox比例风险模型进行风险因素的单因素和多因素分析。分别用0、0.5、1、5、10、20 μmol/L的甲基化抑制剂RG108处理乳腺癌MCF-7细胞5 d后,检测HOXA4 mRNA的表达。 结果基因表达数据芯片分析发现在乳腺癌组织中有1 680个显著上调的基因和1 249个下调基因,整体水平上在不同区域乳腺癌患者甲基化水平较癌旁组织高(P均<0.001)。86例乳腺癌组织中HOXA4基因的甲基化率为94% (81/86),其中,30例高甲基化,52例低甲基化;而在对应癌旁组织中,HOXA4基因甲基化率为57%(49/86),其中49例低甲基化,无高甲基化(P<0.001)。有HOXA4甲基化组的癌组织样本中HOXA4 mRNA表达低于无HOXA4甲基化组的癌组织样本(P＝0.003)。HOXA4基因甲基化水平与乳腺癌淋巴结转移、ER表达有关(P＝0.039、0.017)。单因素分析结果显示患者的TNM分期、组织学分级、淋巴结转移及HOXA4甲基化是DFS的危险因素(RR＝4.008,95%CI＝1.296～12.393,P＝0.016;RR＝10.111,95%CI＝2.607～39.217,P＝0.001;RR＝4.588,95%CI＝1.201～17.523,P＝0.026;RR＝1.051,95%CI＝1.007～1.098,P＝0.024)。多因素分析显示组织学分级是乳腺癌患者DFS的独立预后因素(RR＝14.461,95%CI＝2.429～86.100,P＝0.003)。采用不同浓度的RG108来处理MCF-7细胞后,各组HOXA4 mRNA表达比较,差异有统计学意义(χ²＝4.472,P＝0.029)。 结论HOXA4基因启动子甲基化在乳腺癌的发生、发展中起着重要作用,有潜力作为新的分子生物学指标,用于乳腺癌临床诊断。     

ATR在浸润性乳腺癌组织中的表达和临床意义

目的:探讨共济失调毛细血管扩张突变基因Rad3相关蛋白（ATR）在浸润性乳腺癌组织中的表达及其临床意义。方法:收集289例乳腺癌改良根治术后病理标本,构建组织芯片,采用免疫组化方法检测组织中ATR的表达,并分析其与临床病理参数之间的关系。结果:ATR在乳腺癌组织中的阳性表达率为70.6%（204/289）。ATR阳性表达率在肿瘤直径>2 cm组高于≤2 cm组,在TNM分期Ⅱ-Ⅲ期组高于I期组,在孕激素受体（PR）阳性组高于PR阴性组,在人类表皮生长因子受体2（HER-2）阳性组高于HER-2阴性组,在非三阴性乳腺癌组高于三阴性乳腺癌组,差异均有统计学意义（P<0.05）;ATR的表达与患者发病年龄、月经状态、组织学分级、淋巴结转移情况、雌激素受体（ER）水平、p53状态无明显相关（P>0.05）。结论:浸润性乳腺癌组织中ATR的高表达可能与乳腺癌的进展相关。     

CA IX在乳腺浸润性导管癌中的表达及其临床意义

目的:分析碳酸酐酶IX(CA IX)在乳腺浸润性导管癌组织中的表达及其与临床病理因素的关系。方法:采用免疫组织化学方法检测90例乳腺浸润性导管癌CA IX的表达,比较它们在不同分子分型组织中表达的差异,并分析乳腺浸润性导管癌CA IX的表达与患者年龄,组织学分级及ER、PR、HER-2受体的表达状况等主要病理学特征的关系。结果:CA IX蛋白在乳腺浸润性导管癌的肿瘤细胞上明显高表达,在III-IV期明显高表达于I期和II期（P<0.05）,CA IX 蛋白表达在三阴性型、HER-2型和Luminal型呈逐步明显降低（P<0.05）。结论:CA IX 蛋白特异性高表达于乳腺癌组织上,且肿瘤恶性程度越高,其表达越高。CA IX在乳腺浸润性导管癌的发生发展过程中扮演着重要角色,可能参与肿瘤细胞的增殖、浸润。     

Biological and clinical implications of nicastrin expression in invasive breast cancer

Nicastrin is an essential component of the gamma secretase (GS) enzyme complex, required for its synthesis and recognition of substrates for proteolytic cleavage. The purpose of this study was to investigate whether nicastrin has prognostic value or potential as a therapeutic target in breast cancer (BC). The suitability of nicastrin as a target in BC was assessed using BC tissue microarrays (TMAs) (n = 1050), and its biological role in vitro was evaluated in BC cell lines following gene silencing. Nicastrin blocking antibodies were developed and evaluated for their suitability as potential clinical therapeutics. TMA and cell line analysis confirmed that nicastrin expression was upregulated in BC compared to normal breast cells. In TMA patient samples, high nicastrin expression was observed in 47.5% of cases and correlated with ER?? expression, patient age, and tumor grade. In pre-defined subset analysis, high nicastrin expression predicted for worse BC specific survival in the ER?? ?ve cohort. In vitro gene silencing of nicastrin resulted in disruption of the GS complex and a decrease in notch1 cleavage. This was sufficient to increase E-cadherin expression and its co-localization with p120 catenin at cell?Ccell junctions in MCF7 cells. Nicastrin silencing in invasive MDA-MB-231 cells resulted in loss of vimentin expression and a marked reduction in both cell motility and invasion; which was concomitant with the de novo formation of cell?Ccell junctions characterized by the colocalization of p120 catenin and F-actin. These data indicate that nicastrin can function to maintain epithelial to mesenchymal transition during BC progression. Anti-nicastrin polyclonal and monoclonal antibodies were able to decrease notch1 and vimentin expression and reduced the invasive capacity of BC cells in vitro. This supports our hypothesis that a nicastrin blocking antibody could be used to limit metastatic dissemination in invasive BC.     

FHIT基因在乳腺癌组织中的异常甲基化和表达

目的：检测FHIT基因在乳腺癌组织中的异常甲基化和表达,探讨其在乳腺癌发生发展中的作用。方法：收集乳腺癌新鲜组织标本和配对的癌周正常乳腺标本共90例,采用甲基化特异性PCR和免疫组织化学的方法检测FHIT基因的异常甲基化和蛋白表达。结果：90例乳腺癌组织中,有38例发生了甲基化,阳性率为42％。FHIT基因的甲基化和乳腺癌的临床分期相关,P〈0．01,和淋巴结转移状况不相关,P〉0．05。32例表达FHIT蛋白,阳性率为36％。FHIT蛋白表达和乳腺癌的临床分期以及淋巴结转移状况相关,P〈0．05。FHIT基因的异常甲基化和蛋白表达呈负相关,P〈0．05。结论：FHIT基因的异常甲基化和蛋白失表达是乳腺癌发生、发展过程中的频发事件,两者可以作为预测乳腺癌发展进程的有效标志。甲基化可能是引起FHIT基因失活并进而导致乳腺癌发生的重要机制。     

乳腺浸润性导管癌组织FOXP3表达及其预后意义

目的 叉头框转录因子P3(forkhead box P3,FOXP3)属于叉头框/翼状螺旋转录因子(forkhead box,FOX)家族成员,早期被认为特异性表达于免疫抑制性CD4+ CD25+调节性T细胞(CD4+ CD25+ regulatory T cell,Treg).而近些年来研究发现,FOXP3在多种肿瘤细胞中均有表达.本研究旨在探讨FOXP3在乳腺浸润性导管癌组织中的表达与临床病理学特征的关系及其预后意义.方法 收集2009 01-01-2012-04-30河北医科大学第四医院乳腺中心收治的123例乳腺浸润性导管癌标本,采用免疫组织化学法检测FOXP3蛋白的表达,分析FOXP3与肿瘤临床病理学特征间的关系,并采用Kaplan-Meier法及Cox比例回归风险模型进行生存分析.结果 FOXP3蛋白在乳腺浸润性导管癌实质细胞质和细胞核中均有表达,FOXP3总表达率为68.29％ (84/123).生存分析结果显示,FOXP3表达阳性组的无病生存率(disease free survival,DFS)为89.29％,高于阴性组的71.79％,差异有统计学意义,x2=6.119,P=0.013;但2组的总生存率(overall survival,OS)差异无统计学意义,x2 =1.911,P=0.167.进一步分析FOXP3在乳腺癌细胞中的表达部位发现,FOXP3在细胞核中表达率为47.97％(59/123),细胞质中为63.41％ (78/123).生存分析结果显示,FOXP3细胞核表达阳性组的OS和DFS分别为94.92％和91.53％,均高于细胞核阴性组的82.81％和76.56％,差异均有统计学意义,x2值分别为5.265和4.974,P值分别为0.022和0.026;且Cox多因素分析结果显示,细胞核FOXP3是改善OS的独立预后因素,HR=0.245,P=0.033;但细胞质FOXP3与预后无明显相关性.在FOXP3细胞核表达阳性患者中,无脉管瘤栓组(x2 =5.117,P=0.024)及Ki-67低表达组(x2 =4.214,P=0.041)的表达率更高;且各分子分型间表达率差异有统计学意义,x2=12.983,P=0.002;在Luminal A型乳腺癌中FOXP3细胞核表达率最高,为68.18％.结论 FOXP3在乳腺浸润性导管癌中的预后意义与表达部位相关,细胞核FOXP3高表达是改善乳腺癌OS的独立预后因素,而细胞质FOXP3的表达意义尚不明确.细胞核FOXP3可作为乳腺癌预后良好的预测指标.     

Association of aberrant DNA methylation with clinicopathological features in breast cancer

Aberrant DNA methylation is responsible for the epigenetic silencing of genes associated with tumourigenesis and progression of cancer. In this study, we assessed the methylation status of eight genes in 49 snap-frozen primary breast tumours. Epigenetic alterations of 8 genes were analysed with methylation-specific polymerase chain reaction (MS-PCR) (DCR1, DAPK1, RASSF1A and DCR2) or methylation-sensitive high-resolution melting analysis (MS-HRM) (APC, MGMT, GSTP1 and PTEN). MS-HRM performance was validated by bisulfite pyrosequencing regarding the methylation levels of MGMT. Promoter methylation was observed in APC 54.34%, 40.4% DCR1, 37.5% DAPK1, 33.3% RASSF1A, 22.44% MGMT, 16.6% GSTP1, 6% PTEN and 0% DCR2 promoters, respectively. Interestingly, 37 out of 49 cases (75.5%) displayed aberrant promoter methylation in at least one gene. An association of MGMT promoter methylation with age and tumour grade was recorded. Moreover, a correlation with advanced T-category was elicited for GSTP1, RASSF1 and DAPK1 promoter methylation. Finally, concurrent methylation of several genes showed a marginal statistical relationship with N-category. We conclude that APC, DCR1, DAPK1 and RASSF1A promoter methylation represents a common event in breast cancer tumourigenesis. Our results suggest that GSTP1, RASSF1, DAPK1 and MGMT may be implicated in the acquisition of a more aggressive phenotype in breast cancer.     

Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer

Introduction

Ductal carcinoma in situ (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery. However, it is estimated that about half of the detected lesions would never have progressed into invasive cancer. Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are involved in triggering tumour progression is important for a better understanding of which lesions are at risk of becoming invasive.

Methods

Quantitative DNA methylation analysis of ABCB1, CDKN2A/p16^INK4a, ESR1, FOXC1, GSTP1, IGF2, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A was performed by pyrosequencing in a series of 27 pure DCIS, 28 small invasive ductal carcinomas (IDCs), 34 IDCs with a DCIS component and 5 normal breast tissue samples. FOXC1, ABCB1, PPP2R2B and PTEN were analyzed in 23 additional normal breast tissue samples. Real-Time PCR expression analysis was performed for FOXC1.

Results

Aberrant DNA methylation was observed in all three diagnosis groups for the following genes: ABCB1, FOXC1, GSTP1, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A. For most of these genes, methylation was already present at the DCIS level with the same frequency as within IDCs. For FOXC1 significant differences in methylation levels were observed between normal breast tissue and invasive tumours (P < 0.001). The average DNA methylation levels were significantly higher in the pure IDCs and IDCs with DCIS compared to pure DCIS (P = 0.007 and P = 0.001, respectively). Real-time PCR analysis of FOXC1 expression from 25 DCIS, 23 IDCs and 28 normal tissue samples showed lower gene expression levels of FOXC1 in both methylated and unmethylated tumours compared to normal tissue (P < 0.001). DNA methylation levels of FOXC1, GSTP1, ABCB1 and RASSF1A were higher in oestrogen receptor (ER) positive vs. ER negative tumours; whereas methylation levels of FOXC1, ABCB1, PPP2R2B and PTEN were lower in tumours with a TP53 mutation.

Conclusions

Quantitative methylation analysis identified ABCB1, FOXC1, PPP2R2B and PTEN as novel genes to be methylated in DCIS. In particular, FOXC1 showed a significant increase in the methylation frequency in invasive tumours. Low FOXC1 gene expression in both methylated and unmethylated DCIS and IDCs indicates that the loss of its expression is an early event during breast cancer progression.     

Effect of adjuvant chemotherapy in postmenopausal patients with invasive ductal versus lobular breast cancer

BackgroundOn the basis of the lack of response of invasive lobular breast cancer to neoadjuvant chemotherapy, we questioned the effectiveness of adjuvant chemotherapy in relation to histology.Patients and methodsWomen with primary nonmetastatic invasive ductal or (mixed type) lobular breast cancer, aged 50–70 years, diagnosed between 1995 and 2008, were selected from the Netherlands Cancer Registry and followed until January 1, 2010. The patients were divided in two groups: one group receiving adjuvant hormonal therapy only and the other receiving adjuvant hormonal therapy in combination with adjuvant chemotherapy.ResultsIn total, 19 609 patients had ductal cancer and 3685 had lobular cancer. The 10-year overall survival rate in ductal cancer when treated with hormonal therapy alone was 69%, compared with 74% with the combination therapy (P < 0.0001). In lobular cancer, 10-year survival rates were 68% after hormonal treatment alone and 66% after the combination therapy (P = 0.45). The hazard ratio (HR) for mortality in ductal cancer after combination therapy was 0.70 [95% confidence interval (CI) 0.64–0.76; P < 0.0001], compared with hormonal treatment alone. The HR in lobular cancer was 1.00 (95% CI 0.82–1.21; P = 0.97).ConclusionAdjuvant chemotherapy seems to confer no additional beneficial effects in postmenopausal patients with pure or mixed type lobular breast cancer receiving hormonal therapy.     

Progression from ductal carcinoma in situ to invasive breast cancer: Revisited

Ductal carcinoma in situ (DCIS) is an intraductal neoplastic proliferation of epithelial cells that is separated from the breast stroma by an intact layer of basement membrane and myoepithelial cells. DCIS is a non-obligate precursor of invasive breast cancer, and up to 40% of these lesions progress to invasive disease if untreated. Currently, it is not possible to predict accurately which DCIS would be more likely to progress to invasive breast cancer as neither the significant drivers of the invasive transition have been identified, nor has the clinical utility of tests predicting the likelihood of progression been demonstrated. Although molecular studies have shown that qualitatively, synchronous DCIS and invasive breast cancers are remarkably similar, there is burgeoning evidence to demonstrate that intra-tumor genetic heterogeneity is observed in a subset of DCIS, and that the process of progression to invasive disease may constitute an ‘evolutionary bottleneck’, resulting in the selection of subsets of tumor cells with specific genetic and/or epigenetic aberrations. Here we review the clinical challenge posed by DCIS, the contribution of the microenvironment and genetic aberrations to the progression from in situ to invasive breast cancer, the emerging evidence of the impact of intra-tumor genetic heterogeneity on this process, and strategies to combat this heterogeneity.     

621例乳腺浸润性导管癌患者分子分型与临床病理学特征的关系

目的 探讨新疆地区乳腺浸润性导管癌不同分子亚型的分布,并研究分子亚型与各临床病理学特征的关系。方法 收集2013年1月—2014年1月明确诊断为乳腺浸润性导管癌病例621例,根据雌激素受体(ER)、孕激素受体(PR)、表皮生长因子受体-2(HER-2)和Ki-67的表达情况,把所有病例划分为Luminal A型、Luminal B型、HER-2过表达型及Basal-like型,然后结合临床病理特征进行比较统计。结果 621例中Luminal B型占53.1%,Luminal A型、HER-2过表达型和Basal-like型分别占14.5%、15.9%、16.4%。各分子亚型与肿瘤大小、病理组织学分级、肿瘤病理分期、ER状态、PR状态、HER-2状态均有关(P＜0.05),与年龄、淋巴结状态无关(P＞0.05)。结论 浸润性导管癌患者各分子亚型与其临床病理学特征有密切关系,分子分型有利于指导临床个体化治疗方案的制定。     

Dynamic-enhanced MRI predicts metastatic potential of invasive ductal breast cancer

BACKGROUND: Dynamic magnetic resonance imaging (MRI) has improved the detection of breast malignancies. The method is based on estimating the velocity of contrast enhancement taking into account increased angiogenesis in tumor. Microvessel density correlates with breast carcinoma metastasis. Thus, we hypothesized that contrast enhancement on MRI correlates with metastasis in breast cancer patients. The present study attempts to clarify the quantitative assessment of dynamic data, and examines the correlation between MRI enhancement and breast carcinoma metastasis. METHODS: The subjects consisted of 31 patients with invasive ductal breast cancer. Twenty patients were disease free for five years (group A), and eleven patients suffered from metastatic disease at distant sites concurrently or postoperatively (group B). Dynamic MRI was performed preoperatively using a 1.5T system in all cases. Using the dynamic data, the signal intensity (SI)ratio and SI index were determined and analyzed retrospectively taking into account the presence of distant metastases. RESULTS: The values of the SI ratio were 2.2+/-0.7 in group A and 2.3+/-0.4 in group B, respectively, with no significant difference seen between the groups. The SI index value was significantly higher in group B (28.5+/-32.8) than in group A (10.3+/-5.5, p<0.05). CONCLUSIONS: The current series suggests that the SI index could distinguish patients with high risk of distant metastasis from disease free patients, preoperatively. If a suitable borderline value were established, the quantitative dynamic parameter determined by MRI may be useful for predicting the prognosis of breast cancer patients.     

Severe depression more common in patients with ductal carcinoma in situ than early-stage invasive breast cancer patients

Purpose

Ductal carcinoma in situ (DCIS) is associated with an excellent prognosis; historical studies have shown similar levels of psychological distress in patients with DCIS and with early-stage invasive breast cancer (early-IBC). It is suggested that these results might have led to better patient education about prognosis after DCIS. This study reports the current levels of anxiety, depression, and health-related quality of life (HRQoL) in DCIS and early-IBC patients.

Methods

DCIS (n = 89) and early-IBC patients, T1-2N0, (n = 361) were selected from the UMBRELLA breast cancer cohort. Patient-reported outcomes were prospectively collected before the start of adjuvant radiotherapy (baseline) and at 3, 6, 12, 18, and 24 months thereafter. Mixed models were used to compare differences in levels of anxiety, depression, and HRQoL between DCIS and early-IBC patients.

Results

DCIS and early-IBC patients reported similar levels of anxiety, which were highest at baseline. Depression scores were comparable between groups, also after stratification by use of adjuvant chemotherapy. The proportion of patients reporting high-risk depression scores (i.e., Hospital Anxiety and Depression Sale score >8) was significantly higher among patients with DCIS at 6, 12 and 18 months, and this proportion increased over the first 18 months. Health-related quality of life was comparable between both groups.

Conclusion

Severe depression scores are more common in DCIS patients, despite their excellent prognosis. These results suggest that further improvement of patient education and effective patient doctor communication about the prognostic differences between patients with DCIS and invasive breast cancer is still highly needed.

     

Aromatase inhibition in male breast cancer patients: biological and clinical implications

BackgroundThe role of aromatase inhibitors (AIs) and their impact on estradiol (E₂) levels remain unknown in male breast cancer (MBC) patients.Patients and methodsMBC patients with metastatic disease and those treated with AIs were selected from the breast cancer database of the Centre Antoine-Lacassagne (Nice, France). Sex hormone levels were retrospectively assessed on serum samples from our institutional serum bank.ResultsFifteen patients entered the study. Two patients (13%) had complete response, four patients (27%) had partial response, two patients (13%) had stable disease and seven patients (47%) had progressive disease. The median progression-free survival and overall survival were 4.4 months [95% confidence interval (CI) 0.1–8.6] and 33 months (95% CI 18.4–47.6), respectively. All assessable patients (n = 6) had E₂ levels less than the lower limit of the assay during AI treatment. Among them, three had partial response, one had stable disease and two had progressive disease. A large increase in follicle-stimulating hormone, luteinizing hormone and E₂ levels was observed in one responding patient at progression.ConclusionsAIs are active in MBC patients. This activity is correlated with a significant reduction in E₂ levels. Secondary resistance is in part related to a deleterious feedback loop resulting in a significant increase in substrate for aromatization.     

乳腺浸润性导管癌患者血中PF4和VEGF表达临床意义分析

目的：通过分析乳腺浸润性导管癌患者外周血中血小板因子4（plateletfactor,PF4）和血管内皮生长因子（vas-cularendothelialgrowthfactor,VEGF）的表达与临床病理特征的相关性,探讨其临床意义。方法：选取2012-05-01-2012-07-31河北医科大学第四医院外一科就诊的乳腺浸润性导管癌患者60例作为研究对象,选取同期30名健康女性作为对照。用酶联免疫吸附实验方法检测乳腺浸润性导管癌患者术前及对照组血清PF4和VEGF浓度,分析其表达程度与乳腺浸润性导管癌患者临床病理特征及两者之间的相关性。结果：乳腺浸润性导管癌患者血清PF4表达水平为（0．354±0．198）ng／mL,显著高于对照组的（0．225±0．436）ng／mL,差异有统计学意义,P=0．006;乳腺浸润性导管癌患者VEGF浓度为（15．458±15．819）pg／mL,显著高于对照组的（7．724±8．307）pg／mL,差异有统计学意义,P=0．046。乳腺浸润性导管癌患者组中,血清PF4为0．102～1．117ng／mL,VEGF为0．065～80．85pg／mL,PF4浓度随VEGF浓度的增高而升高,呈显著正相关,r=0．693,P=0．001。在健康对照组中,血清PF4为0．195～0．325ng／mL,血清VEGF为6．768～37．226ng／mL,血清PF4随VEGF浓度的增高而升高,呈显著正相关,r=0．677,P=0．001。有脉管瘤栓患者的血清PF4（0．233±0．089）ng／mL低于无脉管瘤栓者（0．396±0．209）ng／mL,P=0．009。乳腺浸润性导管癌患者血清PF4和VEGF表达与肿瘤大小、TNM分期、淋巴结转移、组织学分化及ER、PR和HER-2蛋白表达无关。结论：血管生成相关因子PF4和vEGF在乳腺浸润性导管癌患者血清中明显升高,可以作为新的判断乳腺癌生物学行为的血清学标志。     

乳腺浸润性导管癌及良性病变中ER基因的5''''CpG岛甲基化状态

目的：探讨ER基因5＇CpG岛甲基化在原发性乳腺癌组织中与ER蛋白失表达的关系及其在肿瘤进展中的作用。方法：用限制性酶、PCR检测45例乳腺浸润性导管癌及15例乳腺良性病变雌激素受体（estrogen receptor，ER）基因中5’CpG岛甲基化状态，甲基化检测结果与免疫组织化学方法检测的ER蛋白表达结果进行比较。结果：在45例乳腺浸润性导管癌中，有20例发生甲基化（44％），其中4例在2个酶切位点均发生甲基化，而其他的只在HpaⅡ位点发生甲基化。15例乳腺良性病变中，无1例发生甲基化。82％ER阳性的乳腺癌组织显示在ER基因中HpaⅡ、HhaⅠ位点均未发生甲基化，而61％ER阴性的乳腺癌组织显示在ER基因中HpaⅡ和（或）HhaⅠ位点发生甲基化，提示免疫组化ER蛋白表达与ER基因5’CpG呈负相关（P〈0．05）。结论：人类乳腺浸润性导管癌中ER基因的5’CpG岛的甲基化与ER蛋白的表达呈负相关，且随组织学分级升高，甲基化发生率增加。     

Proliferation marker securin identifies favourable outcome in invasive ductal breast cancer

We introduce a new proliferation marker, securin (pituitary tumour-transforming 1 (PTTG1)), analysed in invasive ductal breast carcinomas by cDNA microarrays and immunohistochemistry. In cDNA microarray of a total of 4000 probes of genes, securin was revealed with a significant change in expression among the several proliferation-related genes studied. The value of securin as a proliferation marker was verified immunohistochemically (n=44) in invasive ductal breast cancer. In follow-up analyses of the sample of patients, the prognostic value of securin was compared with the established markers of breast cancer proliferation, Ki-67 and mitotic activity index (MAI). Our results of a small sample of patients suggest that low securin expression identifies a distinct subgroup of more favourable outcome among patients with high Ki-67 immunoexpression or high MAI. In univariate analysis of Cox's regression, 10-unit increment of securin immunopositivity was associated with a 2.3-fold overall risk of death due to breast cancer and a 7.1-fold risk of death due to breast cancer in the sample of patients stratified according to the cutoff points of 10 and 20% of securin immunopositivity. We suggest that securin immunostaining is a promising and clinically applicable proliferation marker. The finding urges further prognostic studies with a large sample of patients.     

Immunological subtypes in breast cancer are prognostic for invasive ductal but not for invasive lobular breast carcinoma

Background:

Classical patient and tumour characteristics are the benchmark of personalised breast cancer (BC) management. Recent evidence has demonstrated that immune and molecular profiling of BC may also play an important role. Despite evidence of differences between invasive ductal (IDC) and lobular (ILC) BC, they are infrequently accounted for when making treatment decisions for individual patients. The purpose of this study was to investigate the relevance of the tumour immune response in the major histological subtypes of BC. We also assessed the relationship between immune responses and molecular subtypes and their prognostic potential.

Methods:

Immunostains were done for HLA-I, HLA-E, HLA-G, Tregs, NK cells and CTLs for the composition of the immune profiles and Ki67, EGFR, CK5/6, ER, PR and HER2 for molecular profiles in 714 breast cancer patients who underwent primary surgery.

Results:

No significant association was found between IDC (90.6%) and ILC (9.4%) and tumour immune subtypes (P=0.4) and molecular subtypes (P=0.4). However, for the relapse-free period (RFP) tumour immune subtyping was prognostic (P=0.002) in IDC, but not ILC. Contrary to ILC, IDC patients frequently expressed higher cleaved caspase-3 and Ki67, which was prognostic. Intermediate immune-susceptible IDC expressing high cleaved caspase-3 or Ki67 showed worse RFP than those with low expression (caspase-3: P=0.004; Ki67: P=0.002); this was not seen for ILC or in high or low immune-susceptible tumour types for either IDC or ILC.

Conclusions:

Tumour immune characteristics and host immune responses are prognostic in IDC, but not ILC. In addition, tumour immune profiles are only prognostic in Luminal A tumours.