FOXP3在乳腺浸润性导管癌组织中的表达及其临床意义

发布时间：2018-07-28 21:32

【摘要】：目的:乳腺癌现已成为全球最常见的女性恶性肿瘤,严重影响着女性的身心健康乃至危及生命。乳腺癌的发生涉及原癌基因的活化、抑癌基因的失活等肿瘤启动转化事件,与多基因、多网络、多步骤的信号传导通路调控相关。因此,探究与乳腺癌发生、发展相关的促癌与抑癌基因及其分子机制是现今的研究热点。叉头框转录因子P3(Forkhead box P3,FOXP3)作为叉头/翼状螺旋转录因子家族成员,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在包括乳腺癌在内的多种肿瘤细胞中均有表达,影响着肿瘤的发生、发展。但目前FOXP3在乳腺癌中的表达及意义尚未明确。具体阐明FOXP3在乳腺癌中的作用及其临床预后意义有待更多的实验研究。为此,本研究通过免疫组化Max Vision TM法检测原发性乳腺浸润性导管癌组织中FOXP3的表达情况,进一步探讨FOXP3与乳腺浸润性导管癌患者临床病理特征及预后之间的关系,以期为评估乳腺癌预后提供新指标。方法:1收集2009年1月1日至2012年4月30日河北医科大学第四医院乳腺中心收治的123例初诊原发性乳腺浸润性导管癌患者石蜡标本作为研究对象。随后于我院病理科采用免疫组织化学Max Vision TM法检测组织中FOXP3蛋白的表达情况,并按照最新标准复诊原有病理切片。2结合患者年龄、肿瘤大小、淋巴结转移情况、TNM分期、组织学分级、是否有脉管瘤栓、乳腺癌分子分型、ER/PR、HER-2、Ki-67的表达情况以及患者现存状况的随访结果探讨,FOXP3表达与乳腺癌临床病理特征及预后的关系。3应用SPSS 21.0统计软件进行数据分析。采用卡方检验分析FOXP3与肿瘤临床病理学特征间的关系,Log-Rank法进行生存率差别检,Kaplan-Meier法及Cox比例回归风险模型进行生存分析,探讨FOXP3表达与预后的关系。以P0.05为差异具有统计学意义。结果:1foxp3蛋白在乳腺浸润性导管癌组织中呈弥漫性分布,在乳腺癌细胞核和细胞质中均有表达。胞核和/或胞质foxp3总表达率为68.29%(84/123),胞核foxp3表达率为47.97%(59/123),胞质foxp3表达率为63.41%(78/123)。2根据术后病理是否有脉管瘤栓,将123例患者分为无脉管瘤栓组(86例)和有脉管瘤栓组(37例)。foxp3在两组间的表达差异具有统计学意义,无脉管瘤栓组的foxp3表达率显著高于有脉管瘤栓组,χ2=9.431,p=0.002。3根据ki67表达百分比,以30%为临界值将123例患者分为ki67低表达组(39例)和ki67高表达组(84例)。胞核foxp3在两组间的表达差异具有统计学意义,ki67低表达组的胞核foxp3表达率显著高于ki67高表达组,χ2=4.214,p=0.041。4根据2013年st.gallen早期乳腺癌国际共识,将123例浸润性导管癌进行分子分型:luminala型乳腺癌(22例),luminalb型乳腺癌(44例),her2过表达型乳腺癌(32例),三阴性乳腺癌(25例)。不同分子亚型的foxp3表达状况如下:胞核foxp3在各分子分型间表达有差异(χ2=12.983,p=0.002),在luminala型乳腺癌中表达率最高(68.18%);胞质foxp3在各分子分型间表达有差异(χ2=13.795,p=0.003),三阴性乳腺癌中表达率最高(88.00%)。5foxp3表达与患者年龄、肿瘤大小、淋巴结转移情况、病理分期、组织学分级及her2表达无关(p0.05)。6foxp3表达与预后的关系kaplan-meier生存曲线显示胞核和/或胞质foxp3阳性组的dfs显著高于胞核和/或胞质阴性组(89.29%vs71.79%,log-rank检验χ2=6.119,p=0.013),但两组的os无显著差异(90.47%vs82.05%,log-rank检验χ2=1.911,p=0.167);进一步分析不同表达部位:胞核foxp3阳性组的os和dfs均显著高于胞核阴性组(56/59=94.92%vs52/64=81.25%,log-rank检验χ2=5.265,p=0.022)(54/59=91.53%vs49/64=76.56%,log-rank检验χ2=4.974,p=0.026);而胞质foxp3阳性组与胞质阴性组的os和dfs无显著差异(70/78=89.74%vs38/45=84.45%,log-rank检验χ2=0.856,P=0.355)(69/78=88.46%vs 34/45=75.56%,Log-rank检验χ2=3.502,P=0.061)(Fig.2、Fig.3)。Cox多因素分析亦显示胞核FOXP3表达为改善OS的独立预后因素之一(HR=0.245,P=0.033),而胞核和/或胞质FOXP3表达、胞质FOXP3表达并非是改善OS的独立预后因素(HR=0.431,P=0.124;HR=0.460,P=0.159)。此外,伴有脉管瘤栓是导致较差OS的独立危险因素(HR=2.904,P=0.047)、而ER/PgR表达是改善OS的独立保护因素(HR=0.181,P=0.009)。结论:1胞核FOXP3在无脉管瘤栓组、Ki67低表达组表达率更高,且Luminal A型乳腺癌的胞核FOXP3表达率最高,提示胞核FOXP3的表达与乳腺浸润性导管癌的肿瘤恶性程度呈负相关。2 FOXP3在乳腺浸润性导管癌中的预后意义与表达部位相关,胞核FOXP3表达是改善乳腺癌OS的独立预后因素,而胞质FOXP3的表达意义尚不明确。胞核FOXP3可作为乳腺浸润性导管癌患者预后良好的独立预测指标。
[Abstract]:Objective: breast cancer has now become the most common female malignant tumor in the world, which seriously affects the physical and mental health of women and even endangers life. The occurrence of breast cancer involves the activation of the proto oncogene and the inactivation of tumor suppressor genes, which is related to the regulation of multigene, multi network and multistep signal transduction pathway. P3 (Forkhead box P3 (FOXP3)), a member of the forked / pteric spiral transcription factor family, is believed to be specifically expressed in the immunosuppressive CD4+ CD25+ regulatory T cells (CD4+CD25+regulatory T cell, Treg), as a member of the forked / pterygoid transcription factor family. In recent years, FOXP3 has been found to be expressed in many tumor cells, including breast cancer, affecting the occurrence and development of the tumor. But the expression and significance of FOXP3 in breast cancer are not clear. The role of FOXP3 in breast cancer and the significance of its clinical prognosis need more experimental research. The expression of FOXP3 in primary invasive ductal carcinoma tissue was detected by over immunohistochemical Max Vision TM method, and the relationship between the clinicopathological features and prognosis of patients with FOXP3 and invasive ductal carcinoma was further investigated in order to provide new indicators for evaluating the prognosis of breast cancer. Methods: 1 collection of Hebei medicine from January 1, 2009 to April 30, 2012. The paraffin specimens of 123 patients with primary invasive ductal carcinoma in the breast center of the fourth hospital of the fourth hospital of Ke university were studied. Then the expression of FOXP3 protein in the tissue was detected by immunohistochemical Max Vision TM in the Department of pathology of our hospital. Tumor size, lymph node metastasis, TNM staging, histological classification, whether there were vascular tumor thrombus, the molecular classification of breast cancer, ER/PR, HER-2, Ki-67, and the follow-up results of the patient's status. The FOXP3 expression and the clinicopathological features and prognosis of the breast cancer were analyzed by the.3 application SPSS 21 statistical software. The relationship between the FOXP3 and the clinicopathological features of the tumor was examined, the difference of survival rate between the Log-Rank method, the Kaplan-Meier method and the Cox proportional regression risk model were carried out to analyze the relationship between the expression of FOXP3 and the prognosis. The difference of P0.05 was statistically significant. Results: the 1foxp3 protein was diffuse in the invasive ductal carcinoma of the breast. The sex distribution was expressed in the nucleus and cytoplasm of breast cancer. The total expression rate of nucleus and / or cytoplasm Foxp3 was 68.29% (84/123), the expression rate of nucleus Foxp3 was 47.97% (59/123), and the expression rate of cytoplasmic Foxp3 was 63.41% (78/123).2, and 123 patients were divided into non vascular tumor thrombus group (86 cases) and vascular tumor thrombus group (3) according to postoperative pathology. The expression difference between the two groups was statistically significant in 7 cases. The expression rate of Foxp3 in the non vascular tumor thrombus group was significantly higher than that in the vascular tumor thrombus group. The percentage of Ki67 expressed by 2=9.431, p=0.002.3 was divided into the low expression group of Ki67 (39 cases) and the high expression group of Ki67 (84 cases) with the critical value of 30%. The difference of the expression of nuclear Foxp3 in the two groups was different. With statistical significance, the expression rate of nucleus Foxp3 in Ki67 low expression group was significantly higher than that of Ki67 high expression group. X 2=4.214, p=0.041.4 based on the international consensus of early St.Gallen early breast cancer in 2013, 123 cases of invasive ductal carcinoma were classified into molecular classification: luminala type breast cancer (22 cases), luminal B type breast cancer (44 cases), HER2 overexpressed breast cancer (32 cases), three Negative breast cancer (25 cases). The expression of Foxp3 in the subtypes of different molecular subtypes was as follows: the expression of Foxp3 in the various molecular types was different (x 2=12.983, p=0.002), the expression rate was highest in luminala type breast cancer (68.18%), and the expression of cytoplasmic Foxp3 in each molecular type was different (x 2=13.795, p=0.003), and the highest expression rate in three negative breast cancer (88%). The expression of 5foxp3 was associated with age, tumor size, lymph node metastasis, pathological staging, histological grading and HER2 expression (P0.05) relationship between.6foxp3 expression and prognosis. The Kaplan-Meier survival curve showed that the DFS in the nucleus and / or cytoplasmic Foxp3 positive group was significantly higher than that of the nucleus and / or cytoplasmic negative group (89.29%vs71.79%, log-rank test Chi 2=6.119, p=) 0.013), but there was no significant difference in OS between the two groups (90.47%vs82.05%, log-rank test X 2=1.911, p=0.167). Further analysis of the different expression sites: OS and DFS in the FOXP3 positive group of the nucleus were significantly higher than that of the nuclear negative group (56/59=94.92%vs52/64=81.25%, log-rank test Chi 2=5.265, P) There was no significant difference in the OS and DFS between the cytoplasmic Foxp3 positive group and the cytoplasmic negative group (70/78=89.74%vs38/45=84.45%, log-rank test Chi 2=0.856, P=0.355) (69/78=88.46%vs 34/45=75.56%, Log-rank test Chi 2=3.502, P=0.061) also showed one of the independent prognostic factors to improve the expression of the nucleus. .033), while the expression of nucleus and / or cytoplasmic FOXP3, the expression of cytoplasmic FOXP3 is not an independent prognostic factor for improving OS (HR=0.431, P=0.124; HR=0.460, P=0.159). In addition, the vascular tumor thrombus is an independent risk factor (HR=2.904, P=0.047) that leads to poor OS (HR=2.904, P=0.047), and ER/PgR expression is an independent protective factor for improving the OS. In the non vascular tumor thrombus group, the expression rate of Ki67 low expression group was higher, and the expression rate of FOXP3 in Luminal A type breast cancer was the highest. It suggested that the expression of FOXP3 in the nucleus of the cell nucleus was negatively correlated with the malignant degree of invasive ductal carcinoma of the breast. The prognostic significance of.2 FOXP3 in the invasive ductal carcinoma of the breast was related to the expression site, and the expression of nuclear FOXP3 was the improvement of milk. The independent prognostic factors of adenocarcinoma OS and the expression of cytoplasmic FOXP3 are not clear. Nuclear FOXP3 can be used as an independent predictor of good prognosis for patients with invasive ductal carcinoma of the breast.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R737.9

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