【摘要】：目的:乳腺癌現(xiàn)已成為全球最常見的女性惡性腫瘤,嚴(yán)重影響著女性的身心健康乃至危及生命。乳腺癌的發(fā)生涉及原癌基因的活化、抑癌基因的失活等腫瘤啟動(dòng)轉(zhuǎn)化事件,與多基因、多網(wǎng)絡(luò)、多步驟的信號(hào)傳導(dǎo)通路調(diào)控相關(guān)。因此,探究與乳腺癌發(fā)生、發(fā)展相關(guān)的促癌與抑癌基因及其分子機(jī)制是現(xiàn)今的研究熱點(diǎn)。叉頭框轉(zhuǎn)錄因子P3(Forkhead box P3,FOXP3)作為叉頭/翼狀螺旋轉(zhuǎn)錄因子家族成員,早期被認(rèn)為特異性表達(dá)于免疫抑制性CD4+CD25+調(diào)節(jié)性T細(xì)胞(CD4+CD25+regulatory T cell,Treg),而近些年來研究發(fā)現(xiàn)FOXP3在包括乳腺癌在內(nèi)的多種腫瘤細(xì)胞中均有表達(dá),影響著腫瘤的發(fā)生、發(fā)展。但目前FOXP3在乳腺癌中的表達(dá)及意義尚未明確。具體闡明FOXP3在乳腺癌中的作用及其臨床預(yù)后意義有待更多的實(shí)驗(yàn)研究。為此,本研究通過免疫組化Max Vision TM法檢測(cè)原發(fā)性乳腺浸潤(rùn)性導(dǎo)管癌組織中FOXP3的表達(dá)情況,進(jìn)一步探討FOXP3與乳腺浸潤(rùn)性導(dǎo)管癌患者臨床病理特征及預(yù)后之間的關(guān)系,以期為評(píng)估乳腺癌預(yù)后提供新指標(biāo)。方法:1收集2009年1月1日至2012年4月30日河北醫(yī)科大學(xué)第四醫(yī)院乳腺中心收治的123例初診原發(fā)性乳腺浸潤(rùn)性導(dǎo)管癌患者石蠟標(biāo)本作為研究對(duì)象。隨后于我院病理科采用免疫組織化學(xué)Max Vision TM法檢測(cè)組織中FOXP3蛋白的表達(dá)情況,并按照最新標(biāo)準(zhǔn)復(fù)診原有病理切片。2結(jié)合患者年齡、腫瘤大小、淋巴結(jié)轉(zhuǎn)移情況、TNM分期、組織學(xué)分級(jí)、是否有脈管瘤栓、乳腺癌分子分型、ER/PR、HER-2、Ki-67的表達(dá)情況以及患者現(xiàn)存狀況的隨訪結(jié)果探討,FOXP3表達(dá)與乳腺癌臨床病理特征及預(yù)后的關(guān)系。3應(yīng)用SPSS 21.0統(tǒng)計(jì)軟件進(jìn)行數(shù)據(jù)分析。采用卡方檢驗(yàn)分析FOXP3與腫瘤臨床病理學(xué)特征間的關(guān)系,Log-Rank法進(jìn)行生存率差別檢,Kaplan-Meier法及Cox比例回歸風(fēng)險(xiǎn)模型進(jìn)行生存分析,探討FOXP3表達(dá)與預(yù)后的關(guān)系。以P0.05為差異具有統(tǒng)計(jì)學(xué)意義。結(jié)果:1foxp3蛋白在乳腺浸潤(rùn)性導(dǎo)管癌組織中呈彌漫性分布,在乳腺癌細(xì)胞核和細(xì)胞質(zhì)中均有表達(dá)。胞核和/或胞質(zhì)foxp3總表達(dá)率為68.29%(84/123),胞核foxp3表達(dá)率為47.97%(59/123),胞質(zhì)foxp3表達(dá)率為63.41%(78/123)。2根據(jù)術(shù)后病理是否有脈管瘤栓,將123例患者分為無脈管瘤栓組(86例)和有脈管瘤栓組(37例)。foxp3在兩組間的表達(dá)差異具有統(tǒng)計(jì)學(xué)意義,無脈管瘤栓組的foxp3表達(dá)率顯著高于有脈管瘤栓組,χ2=9.431,p=0.002。3根據(jù)ki67表達(dá)百分比,以30%為臨界值將123例患者分為ki67低表達(dá)組(39例)和ki67高表達(dá)組(84例)。胞核foxp3在兩組間的表達(dá)差異具有統(tǒng)計(jì)學(xué)意義,ki67低表達(dá)組的胞核foxp3表達(dá)率顯著高于ki67高表達(dá)組,χ2=4.214,p=0.041。4根據(jù)2013年st.gallen早期乳腺癌國(guó)際共識(shí),將123例浸潤(rùn)性導(dǎo)管癌進(jìn)行分子分型:luminala型乳腺癌(22例),luminalb型乳腺癌(44例),her2過表達(dá)型乳腺癌(32例),三陰性乳腺癌(25例)。不同分子亞型的foxp3表達(dá)狀況如下:胞核foxp3在各分子分型間表達(dá)有差異(χ2=12.983,p=0.002),在luminala型乳腺癌中表達(dá)率最高(68.18%);胞質(zhì)foxp3在各分子分型間表達(dá)有差異(χ2=13.795,p=0.003),三陰性乳腺癌中表達(dá)率最高(88.00%)。5foxp3表達(dá)與患者年齡、腫瘤大小、淋巴結(jié)轉(zhuǎn)移情況、病理分期、組織學(xué)分級(jí)及her2表達(dá)無關(guān)(p0.05)。6foxp3表達(dá)與預(yù)后的關(guān)系kaplan-meier生存曲線顯示胞核和/或胞質(zhì)foxp3陽性組的dfs顯著高于胞核和/或胞質(zhì)陰性組(89.29%vs71.79%,log-rank檢驗(yàn)χ2=6.119,p=0.013),但兩組的os無顯著差異(90.47%vs82.05%,log-rank檢驗(yàn)χ2=1.911,p=0.167);進(jìn)一步分析不同表達(dá)部位:胞核foxp3陽性組的os和dfs均顯著高于胞核陰性組(56/59=94.92%vs52/64=81.25%,log-rank檢驗(yàn)χ2=5.265,p=0.022)(54/59=91.53%vs49/64=76.56%,log-rank檢驗(yàn)χ2=4.974,p=0.026);而胞質(zhì)foxp3陽性組與胞質(zhì)陰性組的os和dfs無顯著差異(70/78=89.74%vs38/45=84.45%,log-rank檢驗(yàn)χ2=0.856,P=0.355)(69/78=88.46%vs 34/45=75.56%,Log-rank檢驗(yàn)χ2=3.502,P=0.061)(Fig.2、Fig.3)。Cox多因素分析亦顯示胞核FOXP3表達(dá)為改善OS的獨(dú)立預(yù)后因素之一(HR=0.245,P=0.033),而胞核和/或胞質(zhì)FOXP3表達(dá)、胞質(zhì)FOXP3表達(dá)并非是改善OS的獨(dú)立預(yù)后因素(HR=0.431,P=0.124;HR=0.460,P=0.159)。此外,伴有脈管瘤栓是導(dǎo)致較差OS的獨(dú)立危險(xiǎn)因素(HR=2.904,P=0.047)、而ER/PgR表達(dá)是改善OS的獨(dú)立保護(hù)因素(HR=0.181,P=0.009)。結(jié)論:1胞核FOXP3在無脈管瘤栓組、Ki67低表達(dá)組表達(dá)率更高,且Luminal A型乳腺癌的胞核FOXP3表達(dá)率最高,提示胞核FOXP3的表達(dá)與乳腺浸潤(rùn)性導(dǎo)管癌的腫瘤惡性程度呈負(fù)相關(guān)。2 FOXP3在乳腺浸潤(rùn)性導(dǎo)管癌中的預(yù)后意義與表達(dá)部位相關(guān),胞核FOXP3表達(dá)是改善乳腺癌OS的獨(dú)立預(yù)后因素,而胞質(zhì)FOXP3的表達(dá)意義尚不明確。胞核FOXP3可作為乳腺浸潤(rùn)性導(dǎo)管癌患者預(yù)后良好的獨(dú)立預(yù)測(cè)指標(biāo)。
[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.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R737.9

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7 賈鐳;祝領(lǐng);王繼征;王曉建;陳敬洲;宋雷;孫凱;袁祖貽;惠汝太;;FOXP3基因甲基化修飾促進(jìn)動(dòng)脈粥樣硬化進(jìn)程[A];中華醫(yī)學(xué)會(huì)第十五次全國(guó)心血管病學(xué)大會(huì)論文匯編[C];2013年

8 吳燕虹;楊慧蘭;劉仲榮;樊建勇;;CD4+CD25+調(diào)節(jié)性T細(xì)胞及FoxP3表達(dá)在白癜風(fēng)發(fā)病中的作用研究[A];中華醫(yī)學(xué)會(huì)第十五次全國(guó)皮膚性病學(xué)術(shù)會(huì)議論文集[C];2009年

9 謝勇;周南進(jìn);陳江;鄧樂;胡思雋;劉東升;;小鼠幽門螺桿菌感染和根除后Foxp3~+調(diào)節(jié)性T細(xì)胞的變化[A];第六屆全國(guó)免疫學(xué)學(xué)術(shù)大會(huì)論文集[C];2008年

10 黃東暉;甘考;;喘可治注射液誘導(dǎo)哮喘小鼠Foxp3~+調(diào)節(jié)性T細(xì)胞的免疫機(jī)制探討[A];第五屆全國(guó)中西醫(yī)結(jié)合變態(tài)反應(yīng)學(xué)術(shù)會(huì)議論文集[C];2011年

相關(guān)博士學(xué)位論文 前6條

1 褚淑媛;慢性阻塞性肺疾病患者調(diào)節(jié)性T細(xì)胞核轉(zhuǎn)錄因子Foxp3的表達(dá)及單核苷酸多態(tài)性的研究[D];廣西醫(yī)科大學(xué);2013年

2 姜昌麗;FOXP3△2相互作用分子的篩選與鑒定[D];第四軍醫(yī)大學(xué);2009年

3 賈鐳;可可影響血脂譜的薈萃分析及FOXP3基因甲基化修飾與動(dòng)脈粥樣硬化的相關(guān)性研究[D];北京協(xié)和醫(yī)學(xué)院;2011年

4 徐妍;HPV-11E7抗原HLA-A~*0201限制性CTL表位的鑒定和尖銳濕疣患者外周血Foxp3~+CD4~+CD25~+調(diào)節(jié)性T細(xì)胞的表達(dá)[D];浙江大學(xué);2008年

5 孫磊;體外觀察Foxp3及IL-10在人天然CD4+CD25+調(diào)節(jié)性T細(xì)胞中的作用[D];山東大學(xué);2010年

6 魏華興;調(diào)節(jié)性T細(xì)胞在小鼠免疫介導(dǎo)肝炎中的作用及機(jī)理研究[D];中國(guó)科學(xué)技術(shù)大學(xué);2008年

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1 賈存昕;羅非魚Foxp3表達(dá)細(xì)胞及其在實(shí)驗(yàn)性自身免疫性腦脊膜炎（EAE）中的作用[D];西南大學(xué);2015年

2 楊冬倩;Foxp3~+調(diào)節(jié)性T細(xì)胞及IL-10、TGF-β1在播散性毛孢子菌病小鼠模型的動(dòng)態(tài)研究[D];安徽醫(yī)科大學(xué);2015年

3 趙_，

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