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研究生:吳文斌
研究生(外文):Wun-Bin Wu
論文名稱:雌性激素蛋白質胼合物與乳癌預防指標之相關性
論文名稱(外文):Investigation of the association of estrogen-derived protien adducts with predictive biomarkers of breast cancer
指導教授:林伯雄林伯雄引用關係
口試委員:謝為忠柯俊良林家驊
口試日期:2017-06-22
學位類別:碩士
校院名稱:國立中興大學
系所名稱:環境工程學系所
學門:工程學門
學類:環境工程學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:97
中文關鍵詞:蛋白質胼合物乳癌
外文關鍵詞:protein adductsbreast cancer
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  • 被引用被引用:0
  • 點閱點閱:118
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  • 收藏至我的研究室書目清單書目收藏:0
本研究目的為探討台灣乳癌婦女體內血紅蛋白(hemoglobin, Hb)中雌性激素(17β-estradiol, E2)醌類蛋白質胼合物(protein adducts)之背景值與乳癌風險因子如年齡、BMI及與乳癌臨床診療指標,包括乳癌期別(stage)、雌性激素受體 (Estrogen receptor, ER)、黃體激素受體 (Progesterone receptor, PR)、人類表皮生長因子受體2 (human epidermal growth factor receptor 2, HER-2)之相關性分析。結果顯示,本研究新分析之乳癌婦女(n=30)體內血紅蛋白E2-2,3-Q-4-S-Hb及 E2-3,4-Q-2-S-Hb所偵測之平均值(標準偏差)分別365 (193) 及776 (534) pmole/g,跟健康控制組有明顯的5-6倍顯著差異(p <0.001),且其相關性也與本實驗室之前結果相符,並顯示出此一雌性激素醌類蛋白質胼合物作為乳癌生物指標具有高度專一性。
結合本實驗室之前(n=143)及本研究(n=30)所檢測之乳癌病人總共173位,比較分析E2-3,4-Q-2-S-Hb及E2-2,3-Q-4-S-Hb之背景值與乳癌風險因子,包括年齡、BMI、及乳癌臨床診斷及治療指標,包括ER(+)/(-)、PR(+)/(-)、HER2(+)/(-)之相關性,結果顯示皆無顯著之差異,雖然在各期別之乳癌病人間也無任何差異,但良性腫瘤病人之醌類蛋白質胼合物已與乳癌病人約略相當,與健康控制組有明顯的顯著差異(p <0.001)。
綜合以上之分析,人體內血紅蛋白雌性激素醌類蛋白質胼合物E2-2,3-Q-4-S-Hb及 E2-3,4-Q-2-S-Hb可做為乳癌高風險族群之篩檢指標。
The aims of this study were to investigate whether the background levels of 17β-estradiol (E2)-derived quinone protein adducts in human hemoglobin (Hb) associate with the breast cancer risk factors and indicaters of diagnosis and treatment for breast cancer, including Age, BMI, status of disease stage, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2) in Taiwanese women with breast cancer. Results from the analysis indicated that levels of Hb adducts of estrogen quinones, including E2-2,3-Q-4-S-Hb and E2-3,4-Q-2-S-Hb were detected in subjects (n=30) with mean (standard deviation) levels at 365 (193) and 776 (534) pmole/g, respectively. This finding is in consistent with our previous investigation in the measurement of these adducts in breast cancer patients, suggesting that Hb adducts of estrogen quinones are highly specific to breast cancer risk.
Combined our previous investigation (n=143) with current study (n=30), we compared levels of these adducts with risk factors of breast cancer, diagnosis and treatment indicators for breast cancer patients, including age, body mass index, ER(+)/(-), PR(+)/(-), HER2(+)/(-). Results indicated that levels of E2-2,3-Q-4-S-Hb and E2-3,4-Q-2-S-Hb did not correlate with the status of these indicators. Additionally, levels of these adducts are comparable as distinguished by disease stage. Levels of Hb adducts of estrogen quinones in benign tumor patients were similar to those of in malignant tumor patients.
Overall, this evidence suggests that hemoglobin adducts of estrogen quinones may serve as a screening biomarkers for subjects at high risk of developing breast cancer.
摘 要 i
Abstract ii
縮寫表 (List of Abbreviation) iii
目 錄 v
圖目錄 ix
表目錄 xi
第一章 前 言 1
1-1 研究緣起 1
1-2 研究目的 2
第二章 文獻回顧 3
2-1 癌症 3
2-1-1 乳癌 4
2-2乳癌風險因子 9
2-2-1 年齡 9
2-2-2 身體質量指標 (Body Mass Index) 10
2-2-3 種族 11
2-2-4 家族病史 11
2-2-5 生活習慣 12
2-3 雌性激素(Estrogen) 13
2-3-1 雌性激素之代謝機制 15
2-3-2 雌性激素與乳癌 19
2-3-3 乳腺細胞中之受體 20
2-4診斷與治療指標 23
2-4-1 雌性激素受體 (Estrogen receptor, ER) 23
2-4-2 黃體激素受體 (Progesterone receptor, PR) 24
2-4-3 人類表皮生長因子受體2 ( Human Epidermal Growth Factor Receptor 2, Her2) 26
2-4-4 乳癌期別 (Stage)及存活率 28
2-4-5 人類表皮生長因子受體與乳癌轉移復發之關聯 29
2-5 蛋白質胼合物 31
2-5-1 蛋白質腁合物種類 31
2-5-2 生物指標 34
2-5-3 蛋白質腁合物作為生物指標之應用 34
2-6 雌激素代謝之相關酵素與基因多型性 36
2-6-1 細胞色素P450 (CYPs) 36
2-6-2 CYP1A1/CYP1B1 37
2-7 乳癌遺傳基因 38
2-7-1 BRCA1/BRCA2 38
第三章 實驗架構與設計 41
3-1 實驗架構 41
3-2 實驗假設 42
第四章 實驗材料及方法 43
4-1 實驗材料 43
4-1-1 化學品及耗材 43
4-1-2 實驗設備 44
4-2 實驗方法 45
4-2-1全血分離 45
4-2-2 2/4-OH E2 -N-acetyl-L-Cysteine Adducts 之合成 46
4-2-3 2/4-OH E2 -N-acetyl-L-Cysteine Adducts 製備 47
4-2-4 E2–Protein Hb Adducts製備 48
4-2-5 利用17β-Estradiol-2, 4, 16, 16, 17-d5製備雌性激素同位素蛋白質胼合物內標準品 49
4-2-6 TFAA derivatization分析方法 51
4-2-7標準品及樣本透析 52
4-3 氣相層析質譜儀分析條件 54
4-4 統計分析 56
4-5 彰化基督教醫院乳癌婦女之背景資料 57
第五章 實驗結果 60
5-1 彰化基督教醫院乳癌婦女體內血紅蛋白之雌性激素醌類蛋白質胼合物之背景值 60
5-2 彰化基督教醫院乳癌婦女體內血紅蛋白之雌性激素醌類蛋白質胼合物之ER(+)/ER(-)背景值 62
5-3 彰化基督教醫院乳癌婦女體內血紅蛋白之雌性激素醌類蛋白質胼合物之PR(+)/PR(-)背景值 63
5-4 彰化基督教醫院乳癌婦女體內血紅蛋白之雌性激素醌類蛋白質胼合物之HER2(+)/HER2(-)背景值 64
第六章 討論 65
6-1 健康正常人與乳癌病人體內雌性激素醌類之血紅蛋白胼合物之相關性 65
6-2 乳癌病人體內雌性激素醌類之血紅蛋白胼合物與年齡之相關性 68
6-3 乳癌病人體內雌性激素醌類之血紅蛋白胼合物與BMI之相關性……….. 71
6-4 彰化基督教醫院乳癌病人之雌性激素醌類蛋白質胼合物背景值與臨床指標之相關性 73
6-4-1 乳癌病人之雌性激素醌類蛋白質胼合物背景值與ER(+)/ER(-)之相關性 73
6-4-2 乳癌病人之雌性激素醌類蛋白質胼合物背景值與PR(+)/RR(-)之相關性 75
6-4-3 乳癌病人之雌性激素醌類蛋白質胼合物背景值與HER2(+)/HER2(-)之相關性 78
6-5 乳癌病人各期別、良性腫瘤婦女與健康婦女之體內雌性激素醌類蛋白質胼合物背景值E2-2,3-Q-4-S-Hb及E2-3,4-Q-2-S-Hb之相關性。 80
第七章 結論 83
第八章 未來工作與建議 84
參考文獻 85
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