PTEN缺失在乳腺癌發(fā)生發(fā)展中的作用研究
發(fā)布時間：2018-07-25 13:09
【摘要】：目的:乳腺癌是異質(zhì)性腫瘤,由于個體之間基因表達(dá),環(huán)境因素、遺傳因素等的差異性造成乳腺癌的復(fù)雜多樣性。乳腺癌的異質(zhì)性給腫瘤的治療和預(yù)后帶來極大的困難。乳腺癌的其中一個重要致病因素是癌癥基因組發(fā)生改變�；虻母淖円矘�(gòu)成了乳腺癌病理和生理的多樣性。pten基因是抑癌基因,編碼具有雙重磷酸酶活性的PTEN蛋白。研究表明大約50%左右的乳腺癌發(fā)生PTEN的缺失。許多研究報道,PTTEN缺失與乳腺癌的不良預(yù)后有關(guān)。本文探討了 PTEN基因同乳腺癌發(fā)生發(fā)展和預(yù)后之間的聯(lián)系,將為乳腺癌的治療提供理論依據(jù)。方法:綜合TCGA數(shù)據(jù)和meta薈萃分析PTEN缺失與乳腺癌的預(yù)后的關(guān)系。根據(jù)知情同意原則收集云南省昆華醫(yī)院乳腺癌樣品,通過免疫組化方法檢測乳腺癌患者關(guān)鍵蛋白的表達(dá)。構(gòu)建PTEN敲低的乳腺癌細(xì)胞系檢測PTEN缺失對PI3K/AKT/mTOR和Raf/MEK/ERK信號通路的影響。結(jié)果:①TCGA數(shù)據(jù)表明,PTEN突變或PTEN缺失對乳腺癌患者生存沒有顯著影響。②meta分析發(fā)現(xiàn)PTEN缺失與Her2靶向治療Her2陽性乳腺癌患者藥物反應(yīng)率有顯著相關(guān)性(p0.001)。PTEN缺失與曲妥珠單抗靶向治療Her2陽性乳腺癌患者總生存期有顯著相關(guān)性(p=0.006)。PTEN缺失與曲妥珠單抗靶向治療Her2陽性乳腺癌患者無病生存期無顯著相關(guān)性(p=0.460)。③乳腺癌樣品四種分子分型中Luminal A型患者有3例(6%)、Luminal B型患者4例(8%)、Her2陽性型患者23例(46%)、三陰性患者有20例(40%),其中淋巴結(jié)腫大患者為92.6%,淋巴結(jié)轉(zhuǎn)移患者有51.9%,絕大部分患者組織分級為浸潤型導(dǎo)管癌。④乳腺癌分子分型和Bcl2、P53、MMP9、PI3K 110α的表達(dá)量沒有顯著相關(guān)性。⑤乳腺癌樣品中,PTEN蛋白的缺失達(dá)到70%。PTEN表達(dá)量與腫瘤直徑、淋巴結(jié)腫大和淋巴結(jié)轉(zhuǎn)移沒有顯著相關(guān)性。PTEN的表達(dá)量與ER、Ki67、MMP9的表達(dá)量有顯著相關(guān)性(p0.05),但是PTEN的表達(dá)量與PR的表達(dá)量、Her2的表達(dá)量、Bcl2的表達(dá)量、P53的表達(dá)量、PI3K110α表達(dá)量無顯著相關(guān)性(p0.05)。⑥Cas9質(zhì)粒構(gòu)建PTEN敲低的乳腺癌細(xì)胞系發(fā)現(xiàn),PI3K/Akt/mTOR通路中,p-AKTThr308和p-AKT Ser473表達(dá)量升高,p-mTOR Ser2481和p-mTOR Ser2448表達(dá)量也明顯升高。而在Raf/MEK/ERK信號通路中p-MEK1/2和p-ERK1/2表達(dá)量沒有顯著性差異。結(jié)論:TCGA數(shù)據(jù)分析表明PTEN低表達(dá)或PTEN缺失對乳腺癌患者的預(yù)后沒有差異性影響,但是meta數(shù)據(jù)分析顯示在對Her2靶向治療的Her2陽性乳腺癌中,PTEN缺失預(yù)示不良的預(yù)后結(jié)果。免疫組化結(jié)果顯示乳腺癌組織中PTEN缺失達(dá)到70%。乳腺癌組織中MMP9的表達(dá)量高達(dá)72%。在PTEN缺失的樣本中遷移標(biāo)志物MMP9陽性率也顯著高于PTEN正常的樣本,PTEN蛋白表達(dá)量與MMP9的表達(dá)量有顯著相關(guān)性(p=0.028),PTEN缺失與MMP9高表達(dá)有密切聯(lián)系,PTEN缺失的患者淋巴結(jié)轉(zhuǎn)移比率和個數(shù)與PTEN正常的樣本相比呈明顯增高趨勢。說明PTEN在乳腺癌中與腫瘤的遷移和侵襲有著密切的關(guān)系,PTEN可能作為乳腺癌浸潤和轉(zhuǎn)移的標(biāo)志物之一。在PTEN敲低的乳腺癌細(xì)胞系中,PTEN缺失或低表達(dá)激活對PI3K/Akt/mTOR信號通路起激活的作用,對Raf/MEK/ERK信號通路沒有顯著影響。因此PTEN缺失可能在乳腺癌的發(fā)生發(fā)展和預(yù)后中起到關(guān)鍵作用。
[Abstract]:Objective: breast cancer is a heterogeneous tumor. The diversity of breast cancer is caused by the differences in gene expression, environmental factors and genetic factors among individuals. The heterogeneity of breast cancer brings great difficulties to the treatment and prognosis of the tumor. One of the important pathogenic factors of breast cancer is the change of the cancer genome. The pathological and physiological diversity of.Pten is also a tumor suppressor gene, which encodes a PTEN protein with double phosphatase activity. The study shows that about 50% of the breast cancer is missing in PTEN. Many studies have reported that the deletion of PTTEN is related to the poor prognosis of breast cancer. This paper discusses the development and development of the PTEN gene with breast cancer. The relationship between the prognosis will provide a theoretical basis for the treatment of breast cancer. Methods: TCGA data and meta meta analysis of the relationship between PTEN deletion and the prognosis of breast cancer. According to the principle of informed consent, the samples of breast cancer in Kunhua Hospital of Yunnan province were collected, and the expression of key protein in breast cancer patients was detected by immunohistochemical method. The PTEN knockout was constructed. The effects of PTEN deletion on PI3K/AKT/mTOR and Raf/MEK/ERK signaling pathways were detected. Results: (1) TCGA data showed that PTEN mutation or PTEN deletion had no significant influence on the survival of breast cancer patients. (2) meta analysis revealed a significant correlation between PTEN deletion and Her2 targeting therapy for Her2 positive breast cancer patients (p0.001).PT There was a significant correlation between EN deletion and trastuzumab targeting Her2 positive breast cancer patients (p=0.006).PTEN deletion and trastul monoclonal antibody targeting treatment of Her2 positive breast cancer patients without significant correlation (p=0.460). (p=0.460) in the four types of molecular typing of breast cancer, Luminal A patients (6%), Luminal B patients 4 Cases (8%), 23 cases (46%) of Her2 positive patients and 20 cases (40%) of three negative patients, of which lymph node enlargement was 92.6%, lymph node metastases were 51.9%, and most of the patients were classified as invasive ductal carcinoma. (4) there was no significant correlation between the molecular classification of breast cancer and the expression of Bcl2, P53, MMP9, and PI3K 110 alpha. (5) PTEN eggs in breast cancer samples There was no significant correlation between 70%.PTEN expression and tumor diameter, lymph node enlargement and lymph node metastasis. The expression of.PTEN was significantly correlated with the expression of ER, Ki67 and MMP9 (P0.05), but there was no significant correlation between the expression of PTEN and the expression of PR, the expression of Her2, the expression of Bcl2, the P53 expression, and the expression of PI3K110 alpha. P0.05. 6 Cas9 plasmid construction of PTEN knockout breast cancer cell lines found that the expression of p-AKTThr308 and p-AKT Ser473 increased in the PI3K/Akt/mTOR pathway, and the expression of p-mTOR Ser2481 and p-mTOR Ser2448 increased. PTEN low expression or PTEN deletion had no difference in the prognosis of breast cancer patients, but meta data analysis showed that PTEN deletion indicated poor prognosis in Her2 positive breast cancer targeting Her2 targeted therapy. The immunohistochemical results showed that the expression of MMP9 in 70%. breast cancer tissues was up to 72%. in breast cancer tissues as high as 72%.. The MMP9 positive rate of migratory markers in PTEN missing samples was significantly higher than that of the normal PTEN samples. The expression of PTEN protein was significantly correlated with the expression of MMP9 (p=0.028). The deletion of PTEN was closely related to the high expression of MMP9. The ratio and number of lymph node metastases in patients with PTEN deletion were significantly higher than those of normal PTEN samples. PTEN is closely related to tumor migration and invasion in breast cancer. PTEN may be one of the markers for breast cancer invasion and metastasis. In the PTEN knockout breast cancer cell lines, the PTEN deletion or low expression activation plays a role in the activation of the PI3K/Akt/mTOR signaling pathway and has no significant influence on the Raf /MEK/ERK signaling pathway. Therefore PTEN Deletion may play a key role in the development and prognosis of breast cancer.
【學(xué)位授予單位】：昆明理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R737.9
本文編號：2143921
[Abstract]:Objective: breast cancer is a heterogeneous tumor. The diversity of breast cancer is caused by the differences in gene expression, environmental factors and genetic factors among individuals. The heterogeneity of breast cancer brings great difficulties to the treatment and prognosis of the tumor. One of the important pathogenic factors of breast cancer is the change of the cancer genome. The pathological and physiological diversity of.Pten is also a tumor suppressor gene, which encodes a PTEN protein with double phosphatase activity. The study shows that about 50% of the breast cancer is missing in PTEN. Many studies have reported that the deletion of PTTEN is related to the poor prognosis of breast cancer. This paper discusses the development and development of the PTEN gene with breast cancer. The relationship between the prognosis will provide a theoretical basis for the treatment of breast cancer. Methods: TCGA data and meta meta analysis of the relationship between PTEN deletion and the prognosis of breast cancer. According to the principle of informed consent, the samples of breast cancer in Kunhua Hospital of Yunnan province were collected, and the expression of key protein in breast cancer patients was detected by immunohistochemical method. The PTEN knockout was constructed. The effects of PTEN deletion on PI3K/AKT/mTOR and Raf/MEK/ERK signaling pathways were detected. Results: (1) TCGA data showed that PTEN mutation or PTEN deletion had no significant influence on the survival of breast cancer patients. (2) meta analysis revealed a significant correlation between PTEN deletion and Her2 targeting therapy for Her2 positive breast cancer patients (p0.001).PT There was a significant correlation between EN deletion and trastuzumab targeting Her2 positive breast cancer patients (p=0.006).PTEN deletion and trastul monoclonal antibody targeting treatment of Her2 positive breast cancer patients without significant correlation (p=0.460). (p=0.460) in the four types of molecular typing of breast cancer, Luminal A patients (6%), Luminal B patients 4 Cases (8%), 23 cases (46%) of Her2 positive patients and 20 cases (40%) of three negative patients, of which lymph node enlargement was 92.6%, lymph node metastases were 51.9%, and most of the patients were classified as invasive ductal carcinoma. (4) there was no significant correlation between the molecular classification of breast cancer and the expression of Bcl2, P53, MMP9, and PI3K 110 alpha. (5) PTEN eggs in breast cancer samples There was no significant correlation between 70%.PTEN expression and tumor diameter, lymph node enlargement and lymph node metastasis. The expression of.PTEN was significantly correlated with the expression of ER, Ki67 and MMP9 (P0.05), but there was no significant correlation between the expression of PTEN and the expression of PR, the expression of Her2, the expression of Bcl2, the P53 expression, and the expression of PI3K110 alpha. P0.05. 6 Cas9 plasmid construction of PTEN knockout breast cancer cell lines found that the expression of p-AKTThr308 and p-AKT Ser473 increased in the PI3K/Akt/mTOR pathway, and the expression of p-mTOR Ser2481 and p-mTOR Ser2448 increased. PTEN low expression or PTEN deletion had no difference in the prognosis of breast cancer patients, but meta data analysis showed that PTEN deletion indicated poor prognosis in Her2 positive breast cancer targeting Her2 targeted therapy. The immunohistochemical results showed that the expression of MMP9 in 70%. breast cancer tissues was up to 72%. in breast cancer tissues as high as 72%.. The MMP9 positive rate of migratory markers in PTEN missing samples was significantly higher than that of the normal PTEN samples. The expression of PTEN protein was significantly correlated with the expression of MMP9 (p=0.028). The deletion of PTEN was closely related to the high expression of MMP9. The ratio and number of lymph node metastases in patients with PTEN deletion were significantly higher than those of normal PTEN samples. PTEN is closely related to tumor migration and invasion in breast cancer. PTEN may be one of the markers for breast cancer invasion and metastasis. In the PTEN knockout breast cancer cell lines, the PTEN deletion or low expression activation plays a role in the activation of the PI3K/Akt/mTOR signaling pathway and has no significant influence on the Raf /MEK/ERK signaling pathway. Therefore PTEN Deletion may play a key role in the development and prognosis of breast cancer.
【學(xué)位授予單位】：昆明理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R737.9
【參考文獻(xiàn)】
相關(guān)期刊論文 前5條
1 Frederik Holst;;Estrogen receptor alpha gene amplification in breast cancer:25 years of debate[J];World Journal of Clinical Oncology;2016年02期
2 Franco Lumachi;Davide A Santeufemia;Stefano MM Basso;;Current medical treatment of estrogen receptor-positive breast cancer[J];World Journal of Biological Chemistry;2015年03期
3 Wanqing Chen;;Cancer statistics: updated cancer burden in China[J];Chinese Journal of Cancer Research;2015年01期
4 Peter P Stanich;Robert Pilarski;Jonathan Rock;Wendy L Frankel;Samer El-Dika;Marty M Meyer;;Colonic manifestations of PTEN hamartoma tumor syndrome: Case series and systematic review[J];World Journal of Gastroenterology;2014年07期
5 Jing-Wen Lv;Tian-Lin Cheng;Zi-Long Qiu;Wen-Hao Zhou;;Role of the PTEN signaling pathway in autism spectrum disorder[J];Neuroscience Bulletin;2013年06期
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