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研究生:龍嘉麒
研究生(外文):Jia-Chyi, Lung
論文名稱:細胞週期因子與乳癌之基因體不穩定的相關
論文名稱(外文):Chromosomal Genomic Instability is Related to Aberrant Expression of Cell Cycle Regulators in Breast Cancer
指導教授:沈志陽沈志陽引用關係
指導教授(外文):Chen-Yang Shen
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:109
中文關鍵詞:基因體不穩定乳癌細胞週期因子
外文關鍵詞:cell cycle regulatorsgenomic instabilitybreast cancercyclin D1
相關次數:
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  • 下載下載:133
  • 收藏至我的研究室書目清單書目收藏:1
惡性腫瘤是經由眾多基因改變,歷經多步驟過程而產生。在多步驟過程中正常細胞違反細胞正常生長與分化機制,逐漸轉變為癌前期細胞,更進一步大量增生而轉移至身體其他器官。研究發現,細胞中基因體不穩定是造成基因突變的原因,基因體不穩定普遍促成基因組有突變表現型 (mutator phenotype) 的現象,細胞一旦發生這種現象,則導致基因組的基礎突變率大大增加,進而在癌症細胞有眾多基因突變情形。另一方面,因為細胞週期異常與癌症形成有非常強烈的關聯,不正常細胞週期進行,常是導致細胞大量增生的原因,這些細胞週期因子異常也與癌症形成有關。所以本研究想進一步了解,細胞週期因子異常是否與乳癌基因體不穩定的形成有關,故進行此一研究。本研究利用原發性乳癌的組織 (71名個案),探討乳癌基因體不穩定與細胞週期因子蛋白質表現異常的相關性。共分析六個細胞週期因子 (cyclin A、D1、E、RB1、p21、p27),使用組織免疫染色法,評估細胞週期因子在乳癌組織上的表現情形,以了解這些因子的蛋白質在乳癌組織表現是否異常。另外,利用競爭性核酸雜交實驗測量基因體不穩定,以瞭解乳癌染色體變異區域,進一步瞭解乳癌基因體不穩定的程度。研究發現,cyclin D1異常表現與乳癌基因體不穩定有明顯相關(變異區域大於或等於7),有異常表現的16名個案,其中10名 (62%) 個案具有基因體不穩定,相對於未有異常表現的22名個案中,只有6名 (27%) 個案具有基因體不穩定。另一方面,當p27基因沒有表現或表現量低時,具有cyclin D1異常表現的個案比例 (100%) 較無異常表現的個案比例為高 (12%),達到統計顯著水準 (p<0.05)。由這些結果得知,cyclin D1在維持乳癌基因體穩定方面,扮演了很重要的角色。

To account for the accumulation of genomic alterations required for tumor progression, it has been suggested that the genomes of cancer cells are unstable and that this instability results from defective mutators (the “mutator phenotype” theory). To examine the hypothesis that abnormal cell-cycle regulators act as the mutators contributing to genomic instability, the present study, based on primary tumor tissues from 71 patients with breast cancer, was performed to determine whether there was an association between aberrant expression of cell-cycle regulators (cyclin A, cyclin D1, cyclin E, RB1, p21, and p27) and genomic instability. Comparative genomic hybridization was used to measure chromosomal changes, reflecting genomic instability in individual tumors, while immunohistochemistry was used to detect aberrant expression of cell-cycle regulators. Overexpression of cyclin D1 was found to be significantly correlated with increased genomic instability (defined as harboring more than 7 chromosomal changes), with 63% of tumors overexpressing, and 27% of tumors not overexpressing, cyclin D1 showing genomic instability (p<0.05). Interestingly, this relationship was independent of cell outgrowth (as detected by the proliferation marker, Ki-67), and was particularly significant in tumors not expressing p27 or in tumors with detectable RB1. These results suggest that cyclin D1 plays an alternative role in the regulation of genomic stability.

第一章 緒言…………………………………………………………1
第二章 文獻探討……………………………………………………7
第一節 基因體不穩定………………………………………………7
壹、定義…………………………………………………………….8
貳、基因體不穩定的種類………………………………………….8
參、影響基因體不穩定的原因…………………………………….11
第二節 乳癌之基因體不穩定………………………………………19
壹、現有之基因體不穩定的種類………………………………….19
貳、與乳癌基因體不穩定相關的基因…………………………….24
第三節 細胞週期因子異常在乳癌的探討…………………………26
壹、細胞週期因子cyclin A、D1、E、RB1、p21、p27
與Ki-67的探討……………………………………………….. 26
貳、細胞週期因子cyclin A、D1、E、RB1、p21、p27
異常與乳癌的關係……………………………………………. 29
第四節 乳癌形成原因與病理分類……………………………… 34
壹、乳癌的病理分類……………………………………………….34
貳、乳癌的描述流行病學………………………………………….39
參、乳癌危險因子的探討………………………………………….40
第三章 研究目的……………………………………………………46
第四章 研究假說與研究材料及方法………………………………47
第一節 研究假說………………………………………………… 47
第二節 研究材料及方法……………………………………………48
壹、研究樣本……………………………………………………….48
貳、組織DNA萃取……………………………………………….. 49
參、正常人血液DNA萃取……………………………………….. 50
肆、競爭性核酸雜交法 (CGH)…………………………………… 51
伍、組織免疫染色法 (IHC)……………………………………….53
陸、統計分析……………………………………………………….55
第五章 結果…………………………………………………………56
第一節 基本變項在研究族群分布情形……………………………56
第二節 CGH與基因體不穩定的定義……………………………… 57
第三節 細胞週期因子蛋白質在癌症細胞表現情形………………58
第四節 細胞週期因子與基因體不穩定的相關……………………60
第五節 細胞週期因子間交互作用與基因體不穩定的相關………61
第六節 基因體不穩定與臨床病理的相關…………………………62
第七節 女性賀爾蒙暴露對基因體不穩定的相關…………………62
第六章 討論…………………………………………………………63
第一節 乳癌基因體不穩定的測量…………………………………64
第二節 細胞週期因子在乳癌的表現情形…………………………65
第三節 細胞週期因子與基因體不穩定的相關……………………66
壹、時序性………………………………………………………… 66
貳、Cyclin D1蛋白異常並不伴隨基因增幅而產生..……………67
參、CGH結果無呈現cyclin D1基因區域有異常……………….. 67
第四節 細胞週期因子間交互作用明顯……………………………69
第七章 結論…………………………………………………………71
第八章 參考文獻……………………………………………………82

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行政院務生署 : 中華民國八十七年衛生統計 : 生命統計(二),民國八十八年。
行政院衛生署 : 中華民國八十七年癌症登記報告,民國九十年。

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