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研究生: 劉思婧
Liu, Szu-Ching
論文名稱: 利用4T1 乳癌轉移之小白鼠模式探討獨居引發之焦慮對於乳癌生長的影響
Effect of isolation-induced anxiety on the growth of breast cancer in the mouse 4T1 metastatic model
指導教授: 蔡美玲
Tsai, Mei-Ling
學位類別: 碩士
Master
系所名稱: 醫學院 - 生理學研究所
Department of Physiology
論文出版年: 2018
畢業學年度: 106
語文別: 中文
論文頁數: 50
中文關鍵詞: 焦慮乳癌獨居DHEA
外文關鍵詞: anxiety, breast cancer, social isolation, DHEA
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  • 心理壓力與乳癌的生長和死亡率具有正相關,長期的心理壓力會造成精神上的疾病,像是焦慮症與憂鬱症。以獨居作為引起焦慮方法多用在公鼠的實驗中,實驗發現母鼠獨居較不易引起類似焦慮行為。而在卵巢切除小鼠中給予雌激素與雌激素受體beta活化劑皆可降低小鼠類似焦慮行為表現,顯示雌激素可透過雌激素受體beta降低齧齒類動物類似焦慮行為表現。此外在大鼠動物實驗中發現,獨居引起焦慮後,自發性乳癌的腫瘤大小與腫瘤惡性程度皆顯著增大;在小鼠卵巢癌實驗中也發現獨居引發焦慮後增加腫瘤大小與轉移。然而,與臨床上乳癌病患焦慮情形不同的是,在臨床上,乳癌病人焦慮情況是出現在乳癌診斷後出現,而非焦慮後罹患乳癌。綜合以上資訊,本研究以獨居作為誘導小鼠焦慮之同時引發乳癌產生,探討獨居引發之焦慮對於乳癌生長的影響。本研究利用舉臂式十字迷宮測量小鼠類似焦慮行為表現。為了後續實驗分析,首先比較重複測量舉臂式十字迷宮是否會影響實驗結果,結果顯示重複測量會降低小屬於十字迷宮中活動力,因此為了避免重複測量對實驗結果分析的影響,實驗僅比較相同時間點不同組別間的差異。依研究主題,設計實驗。目的一:探討雌激素對焦慮之影響。由於母鼠在成熟後會開始動情週期,體內雌激素會隨動情週期改變,因此首先需先釐清成熟母鼠卵巢切除,對舉臂式十字迷宮測量中類似焦慮行為表現之影響,以及卵巢切除對獨居母鼠類似焦慮行為之影響。目的二: 探討雌激素化合物補充對類似焦慮行為表現之影響,目的三: 探討腫瘤移植對母鼠類似焦慮行為表現之影響。目的四:探索乳癌細胞生長與焦慮間的關係。以獨居誘導小鼠類似焦慮行為增加的模式觀察乳癌細胞生長與獨焦慮間的結果顯示,獨居一週使開放空間與封閉空間活動力下降,獨居三週使封閉空間的活動力下降。卵巢切除不影響類似焦慮行為表現,但卵巢切除之獨居母鼠獨居一週會降低開放區域活動力與停留時間,獨居三週降低開空間與封閉空間活動力、開放空間停留時間,增加類似焦慮行為表現。雌激素補充三週並無降低小鼠類似焦慮行為表現,但DHEA給予三週則有降低小鼠類似焦慮行為的效果。腫瘤移植三週在群居小鼠腫瘤大小較獨居小鼠大;而四週腫瘤移植腫瘤大小在群居與獨居小鼠相似,且皆有轉移情況出現;腫瘤移植到六週,獨居小鼠腫瘤大小較群居小鼠大,且獨居與群居小鼠皆有死亡情況出現。由於實驗目的欲瞭解獨居對腫瘤生長的影響,後續實驗選擇以腫瘤移植三週進行。腫瘤移植小鼠獨居一週會降低進入開放空間與停留時間,並降低於開放空間活動力;腫瘤移植小鼠獨居三週會降低開放空間與封閉空間活動力。但卵巢切除之腫瘤鼠於獨居後,僅在獨居一週降低進入開放空間次數與開放空間活動力,與無腫瘤卵巢切除獨居小鼠相比並無增加類似焦慮行為表現,並且腫瘤生長在獨居小鼠皆是受到抑制。可體松類似物dexamethasone給予三週可抑制乳癌細胞生長,因此可推測卵巢切除腫瘤移植獨居小鼠腫瘤生長受抑制是受到壓力賀
    爾蒙增加造成。

    SUMMARY
    Chronic stress mostly cause anxiety and is positive relative to breast tumor progression and mortality rate. Rodent studies showed that estrogen reduced anxiety-like behavior through an estrogen receptor beta. The purpose in this study is to investigate whether estrogen removal by ovariectomy in female mice enhanced social isolation induced anxiety-like behavior, and whether social isolation induced anxiety-like behavior promote breast cancer cells progression. Results showed that social isolation induced anxiety-like behavior. Ovariectomy enhance isolation induced anxiety-like behavior. DHEA reduced anxiety-like behavior in ovariectomized mice, but not in tumor transplanted mice. However, tumor transplanted enhanced anxiety-like behavior in intact social isolation mice, but not in ovariectomized social isolation mice. Breast tumor progression were inhibited in social isolation mice, and in tumor transplanted mice DHEA administration did not influence in breast tumor progression.
    Key words: anxiety, breast cancer, social isolation, DHEA

    中文摘要………………………………………………………………………………I 英文延伸摘要………………………………………………………………………II 誌謝……………………………………………………………………………………V 目錄…………………………………………………………………………………VI 表目錄……………………………………………………………………………VIII 圖目錄……………………………………………………………………………IX 1. 文獻探討…………………………………………………………………………1 1-1. 乳腺組織的發育…………………………………………………………1 1-1-1. 賀爾蒙調控乳腺細胞生長………………………………………1 1-2. 乳癌的產生………………………………………………………………2 1-2-1. 乳癌的危險因子…………………………………………………2 1-3. 焦慮和乳癌………………………………………………………………3 1-3-1. 焦慮和賀爾蒙的改變……………………………………………3 1-3-2. 焦慮和雌激素……………………………………………………4 1-3-3. 焦慮與乳癌………………………………………………………4 2. 研究動機…………………………………………………………………………6 3. 材料方法…………………………………………………………………………7 3-1. 細胞株及培養………………………………………………………………7 3-2. 動物照護……………………………………………………………………7 3-3. 焦慮小鼠模式………………………………………………………………7 3-4. 腫瘤移植……………………………………………………………………7 3-5. 舉臂式十字迷宮測試………………………………………………………7 3-6. 非侵入式3D全光譜活體分子影像系統…………………………………8 3-7. 資料分析及統計……………………………………………………………8 4. 實驗結果…………………………………………………………………………9 4-1. 描述在母鼠獨居誘導的類似焦慮行為之特…………………………9 (Characterization of Isolation-induced anxiety like behaviors in female mice) 4-1-1. 重複測量對舉臂式十字迷宮結果的影響………………………9 4-1-2.獨居一週與三週對卵巢切除母鼠類似焦慮行為的影響…………9 4-2. 描述雌激素對卵巢切除小鼠類似焦慮行為表現的影響………………10 (Characterization of estrogen on anxiety like behaviors in ovariectomized mice) 4-2-1.雌激素化合物給予對卵巢切除群居小鼠類似焦慮行為的響…10 4-2-2.雌激素化合物對卵巢切除獨居小鼠類似焦慮行為的影響…11 4-3. 描述在母鼠腫瘤誘導的類似焦慮行為之特性……………………11 (Characterization of tumor-induced anxiety like behaviors in female mice) 4-3-1.卵巢切除喜鼠腫瘤生長特性……………………………………11 4-3-2.獨居一週與三週對腫瘤移植小鼠類似焦慮行為的影響………12 4-3-3.獨居對腫瘤移植小鼠體重增加的影響…………………………13 4-3-4.獨居對腫瘤生長的影響…………………………………………13 4-4. DHEA對獨居所誘導卵巢切除腫瘤移植小鼠類似焦慮行為的影響……13 (Possible involvement of DHEA on isolation-induced anxiety like behaviors in ovariectomized mice with implanted tumor) 4-4-1. DHEA隨時間對卵巢切除腫瘤移植獨居小鼠類似焦慮行為的影響 ……………………………………………………………………13 4-4-2. Dexamethasone給予對卵巢切除腫瘤移植小鼠類似焦慮行為的影響………………………………………………………………14 5. 討論………………………………………………………………………………15 6. 結論………………………………………………………………………………17 7. 參考資料…………………………………………………………………………18 8. 表格………………………………………………………………………………21 9. 圖片………………………………………………………………………………22

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