台灣地區近二十年來女性乳癌的發生率與死亡率有明顯上升的趨勢，已成為重要的公共衛生問題。在乳房組織中，女性賀爾蒙代謝會產生catechol estrogen (CE)和catechol estrogen-quinone (CE-Q)，其會與DNA鍵結產生去嘌呤結合物 (depurinating adducts)，造成基因體的不穩定，另一方面這些quinone產物也參與一些氧化還原反應，產生具自由基的產物，會造成DNA氧化性傷害，這些傷害都可能和乳癌的發生有關。體內對於女性賀爾蒙代謝物有一系列的去毒系統，都是利用結合反應來進行，為了探討此一系統的重要性進一步評估賀爾蒙攻擊DNA起始乳癌發生的可能，本研究假設代謝CE的COMT、SULT、UGT，去除自由基的MnSOD以及將quinone去毒的GST，可能在乳癌發展過程中扮演一個十分重要的角色。
為了檢驗此一假說，我們自共選取268位確診為原發性乳癌病例與384位參加乳房篩檢的健康對照進行病例對照研究，以探討基因多形性與乳癌之相關，研究的基因型變異包括COMT (Val108/158 Met)、SULT1A1 (Arg213His)、UGT1A1 [(TA)nTAA]、 GSTM1 (active/null)、GSTT1 (active/null)和MnSOD (Val-9Ala與Ile58Thr)。我們先利用聚合連鎖反應，再以(1)限制片段長度多形性分析、(2)質量光譜分析(MALDI-TOF MS)、(3) 小片段重複序列分析來判讀個案基因型，最後以非配對資料對數複迴規模式進行單變項和多變項分析，以瞭解女性乳癌與女性賀爾蒙代謝物去毒基因多形性之相關，並探討女性賀爾蒙與基因多形性之交互作用在乳癌致病機轉中所扮演的角色。
研究結果顯示，基因多形性的獨立作用並沒有顯著增加乳癌危險性，但是發現Quinone去毒基因 (MnSOD、GSTT1、GSTM1) 三者皆異常時，顯著增加2.24倍乳癌危險性 (95%信賴區間為1.12-4.51)，同樣地，上下游代謝路徑 (UGT1A1、MnSOD、GSTT1) 間對乳癌危險性的共同作用 (joint effect) 更明顯，OR值高達4.22倍。我們更發現這些去毒基因多形性與懷孕或肥胖等代表賀爾蒙暴露的環境因子對乳癌危險性有顯著之交互作用。有趣的是，對於懷孕來說，上游的CE代謝路徑對乳癌較重要，而對肥胖因子，則是下游代謝去毒quinone的路徑較重要。進一步的分析則發現位在上、中、下游各一個代謝基因異常的路徑與懷孕或肥胖間也有明顯的交互作用，從這些結果都支持了女性賀爾蒙暴露會經由代謝異常的機轉導致DNA傷害而起始乳癌。

The incidence and mortality of breast cancer in Taiwan have been increasing during recent two decades. It has been the second leading cause of cancer incidence among Taiwanese women and has become an issue of particular public health importance. Cumulative, excessive lifetime exposure to estrogen has been documented to be the most important risk factor for breast cancer development. Estrogen has recently attracted considerable attention because of findings suggesting that it can cause DNA damage and mutation. In this initiating effect, the oxidative metabolism of estrogen, firstly to catechol estrogen (CE) 4-hydroxyestradiol, then to a further oxidized metabolite, E2-3,4-quinone, plays a critical role, as in vitro experiments have shown that these metabolites can bind to DNA to form adducts, leading to mutation and genomic deletion during tumorigenesis. In addition to the direct effect, the generation of reactive oxidative species (ROS) during estrogen metabolism may also lead indirectly to oxidative DNA damage. To prevent attack from these estrogen-derived carcinogenic metabolites and maintain genomic stability, the detoxification mechanism via enzyme-mediated conjugation has been suggested to play an important role. Given these clues, this study, aiming at defining possible initiating of estrogen during breast tumorigenesis, hypothesizes that genotypic polymorphisms of CE-conjugating genes (COMT, SULT and UGT), CE-Q-detoxifying genes (GSTM1 and GSTT1), and free radical-scavenger (MnSOD) are associated with an increased of breast cancer risk.
A case-control study of 286 primary breast cancer patients and 384 healthy controls was conducted. The genotypic polymorphisms assayed included COMT (Val108/158 Met), SULT1A1 (Arg213His), UGT1A1 [(TA)nTAA], GSTM1 (wt/null), GSTT1 (wt/null), and MnSOD (Val-9Ala and Ile58Thr), and PCR-RFLP, MALDI-TOF massarray, and ABI Prism 3100 DNA Sequencer were used to determine the genotypes. Unconditional logistical regression models were used to examine both independent effects of individual genes and positive joint/interactive effects between gene and gene or between gene and risk factors reflecting estrogen exposure.
Breast cancer risk in association with individual susceptibility genotypes were found to be not significant. However, when the genes participating the same pathway were considered together, the joint effects in association with increased cancer risk, contributed by CE-Q-detoxifying genes MnSOD,GSTT1, and GSTM1, become statistically significant. Furthermore, the interactions between genes and hormone-related risk factors can be demonstrated by the findings that the associations between increased cancer risk and genotypic polymorphisms are significant only in particular subgroups of women having no history of full-term pregnancy or obese women. These results suggest the existence of combined tumorigenic effects of the estrogen-detoxifying pathway and their interaction with estrogen exposure. In conclusion, our study not only demonstrates estrogen-detoxifying genes are associated with increasing risk of developing breast cancer, but it also supports an initiating role of estrogen during breast tumorigenesis.

目 錄
頁碼
中文摘要………………………………………………………………………………I
英文摘要……………………………………………………………………………...II
目錄……………………………………………………………………………...…...IV
表次…………………………………………………………………………………..VI
圖次………………………………………………………………………………...VIII
第一章 前言 1
第二章 文獻回顧 3
第一節 女性賀爾蒙簡介 3
第二節 女性賀爾蒙與乳癌之相關研究 5
第三節 女性賀爾蒙代謝與乳癌致病機轉 6
第四節 女性賀爾蒙代謝物去毒機制 10
第五節 女性賀爾蒙代謝物去毒基因多形性相關研究 13
第三章 計畫緣起與目的 19
第四章 材料與方法 20
第一節 研究個案選取與血液檢體收集 20
第二節 問卷設計與資料收集 21
第三節 DNA萃取及定量 21
第四節 聚合連鎖反應 (PCR) 23
第五節 限制片段長度多形性分析 (RFLP) 26
第六節 多重聚合連鎖反應 (Multiplex PCR) 27
第七節 質量光譜分析 (MALDI-TOF MS) 28
第八節 小片段重複序列分析 (short-tandem repeats analysis) 30
第九節 資料處理與統計分析 31
第五章 結果 32
第一節 研究個案之基本人口學特徵 32
第二節 危險因子與女性乳癌的關係 33
第三節 女性賀爾蒙代謝物去毒基因多形性對乳癌之易感受性 34
第四節 女性賀爾蒙代謝物去毒基因多形性之間對乳癌之共同影響 36
第五節 女性賀爾蒙代謝基因多形性與環境因子對乳癌之交互作用 38
第六章 討論 42
第七章 總結與未來展望 49
參考文獻 53

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