臺灣博碩士論文加值系統

本研究目的為，同步分析台灣乳癌病人五年術後無復發(5 年存活者)之血清白蛋白(albumin, Alb)與雌激素醌類代謝物胼合物(estrogen quinine):包括17β-estradiol-2,3-quinone(17β-雌二醇-2,3-醌(E2-2,3-Q)) and 17β-estradiol-3,4-quinone (E2-3,4-Q) (17β-雌二醇-3,4-醌(E2-3,4-Q))。5 年存活者血液樣本經由收集後，分析血清白蛋白及紅血球蛋白之雌性激素醌類代謝物(E2-3,4-Q及 E2-3,4-Q)之胼合物背景值，並與治療前之乳癌病人背景值互相比較其差異。研究結果顯示，5 年存活者皆可偵測到E2-2,3-Q-4-S-Alb與E2-3,4-Q-2-S-Alb 雌激素醌胼合物之背景值，且自然對數轉換後之E2-2,3-Q-4-S-Alb與E2-3,4-Q-2-S-Alb呈現正相關 (相關係數 r = 0.628, p<0.001)。其中算術平均值之E2-2,3-Q-4-S-Alb 和 E2-3,4-Q-2-S-Alb背景值為259 and 138 (pmol/g)。經與診斷術前後治療的乳癌病人相比，乳癌存活者的雌激素醌類代謝物之蛋白質胼合物 (E2-2,3-Q-4-S-Alb 和 E2-3,4-Q-2-S-Alb總和) 比手術與治療前的乳癌病人平均值降低90% (p<0.001)。
本研究結果證實，雌性激素醌類代謝物之累積量是乳癌罹患風險及乳癌復發風險之重要指標。此一研究結果證實，乳癌治療療程包括荷爾蒙治療(aromatase inhibitor 及tamoxifen)和環境因素之組合，包括生活習慣及和飲食搞變，可以調節雌激素體內的代謝平衡，並將減少乳癌存活者中雌激素活性醌類代謝物的產生，降低乳癌復發的可能。

The aim of this study was to simultaneously analyze estrogen quinone-derived adducts profile, including 17β-estradiol-2,3-quinone (E2-2,3-Q) and 17β-estradiol-3,4-quinone (E2-3,4-Q), in human albumin (Alb) derived from breast cancer patients with five year postoperative treatment without recurrence (5-year survivors) in Taiwan. Blood samples derived from breast cancer 5-year survivors without recurrence were collected. We analyzed the albumin and hemoglobin adducts of E2-3,4-Q and E2-2,3-Q as biomarkers for evaluation of disposition of estrogen to quinones and compared the estrogen quinone levels with those in patients before treatment. Our result confirmed that both E2-2,3-Q- and E2-3,4-Q-derived adducts, including E2-2,3-Q-4-S-Alb, E2-3,4-Q-2-S-Alb, were detected in all 5-year survivors. Logged levels of E2-2,3-Q-derived adducts correlated significantly with those of E2-3,4-Q-derived adducts (correlation coefficient r = 0.624, p<0.001). Mean levels of E2-2,3-Q-4-S-Alb and E2-3,4-Q-2-S-Alb were estimated to be at 249 and 52 (pmol/g), respectively. This translated to more than 90% reduction in mean values of estrogen quinone-derived adducts (E2-2,3-Q plus E2-3,4-Q) in breast cancer 5-year survivors compared to those in the breast cancer patients with less than one year of diagnosis/preoperative treatment (p<0.001).
Our findings add support to the theme that cumulative body burden of estrogen quinones is an important indicator of breast cancer risk and breast cancer recurrence risk. Hormonal therapy including aromatase inhibitors and Tamoxifen may dramatically reduce burden of estrogen quinones. We hypothesize that combination of treatment-related effects and environmental factors, including changes in life style and diet, may modulate estrogen homeostasis and diminish the production of estrogen quinones in breast cancer 5-year survivors.

目 錄
摘要………………………………………………………………………………….i
Abstract…………………………………………………………………………......ii
目錄…………………………………………………………………………………iii
表目錄……………………………………………………………………………...vii
圖目錄……………………………………………………………………………..viii
縮寫表(List of Abbreviation).....................................................................................x
第一章 前言……………………………………………………………………1
1-1 研究緣起………………………………………………………………….1
1-2 研究目的………………………………………………………………….1
第二章 文獻回顧………………………………………………………………2
2-1 乳癌現況………………………………………………………………….2
2-1-1 台灣乳癌現況…………………………………………………………..3
2-1-2 認識乳癌………………………………………………………………..4
2-2 內分泌與乳房………………………………………………………….4
2-2-1 荷爾蒙或賀爾蒙………………………………………………………..5
2-3 影響因子……………………………………………………………….7
2-3-1 家族性影響……………………………………………………………8
2-3-2 環境賀爾蒙影響………………………………………………………8
2-4 雌激素(Estrogen)……………………………………………….........9
2-4-1 雌性激素結構(Estrogen)……………………………………………10

 
2-4-2 雌性激素代謝………………………………………………………10
2-4-3 雌性激素代謝之致癌機制…………………………………………12
2-4-4 雌性激素代謝平衡…………………………………………………13
2-4-5 雌激素代謝之酵素…………………………………………………14
2-4-6 雌性激素與乳癌……………………………………………………16
2-5 蛋白質胼合物(Protein adducts)……………………………………17
2-6 生物指標(Biomarkers)……………………………………………...19
2-6-1 生物指標之蛋白質胼合物應用……………………………………..20
2-6-2 血清蛋白……………………………………………………………..21
2-7 乳癌治療指標………………………………………………………...22
2-7-1 雌性激素受體(Estrogen receptor,ER)……………………………..23
2-7-2 黃體激素受體(Progesterone receptor,PR)………………………...24
2-7-3 人類表皮生長因子受體2( Human Epidermal Growth Factor
Receptor 2, Her2)………………………………………………….25
第三章 實驗架構與研究假設............................................................................26
3-1 環境毒理實驗室取得Protein adducts之實驗架構………………..26
3-2 研究假設………………………………………………………………27
第四章 實驗材料及方法……………………………………………………...28
4.1 實驗材料……………………………………………………………28
4-1-1 化學藥品及耗材……………………………………………………28
4-1-2 實驗設備……………………………………………………………29
4-2 實驗方法…………………………………………………………...30
4-2-1 血清白蛋白之透析…………………………………………………31
4-2-2 E2-N-acetyl-L-Cysteine Adducts製備…………………………….32
4-2-3 E2-HAS Adducts製備……………………………………………...33


4-2-4 利用17β-Estradiol-2, 4, 16, 16, 17-d5製備雌性激素同位素白質胼
合物內標準品………………………………………………………..34
4-2-5 TFAA derivatization分析方法…………………………………….36
4-3 氣相層析質譜儀分析條件…………………………………………...38
4-4 統計分析……………………………………………………………...40
第五章 實驗結果………………………………………………………………41
5-1 彰化基督教醫院及苗栗大千醫院五年存活乳癌病人體內雌性激素醌
類血清白蛋白質胼合物定性定量607m/z、610m/z、611m/z之偵測
量……………………………………………………………………...41
5-2 彰化基督教醫院及苗栗大千醫院乳癌病人體內雌性激素醌類血清
白蛋白質胼合物之背景值…………………………………………...42
5-3 年齡區間上雌性激素醌類血清白蛋白胼合物之背景值…………..44
5-4 乳癌病人年齡背景值之體內雌性激素醌類血清白蛋白質胼合物
E2-3,4-Q-2-S- Alb,E2-2,3-Q-4-S-Alb………………………………..45
第六章 討 論……………………………………………………………….....46
6-1 彰化基督教醫院與苗栗大千醫院乳癌病人體內雌性激素醌類血清
白蛋白質胼合物…………………………………………………….46
6-2 不同年齡區間之體內雌性激醌類血清白蛋白質胼合物背景差異相
關性質……………………………………………………………….47
6-3 彰化基督教醫院與苗栗大千醫院之血液樣本中血清白蛋白胼合物
對照結果…………………………………………………………….50
 
6-4 使用AI及Tamoxifen之乳癌病人5年存活者與健康者及手術後病
人其雌性激素醌類血清白蛋白質胼合物相較差異性……………51
第七章 結 論………………………………………………………………..53
參 考 文 獻……………………………………………………………………54

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