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標題: 探討雄激素累積與雄激素受體活化在Anastrozole抑制乳癌細胞生長的反應中扮演的角色
Investigation of androgen accumulation and androgen receptor activation in Anastrozole-induced growth inhibition of breast cancer cells
作者: 白家明
Pai, Chia-Ming
關鍵字: 雌激素受體;Breast cancer;芳香酶抑制劑;Bcl-2;cyclin D1;雄激素受體;細胞增生;ER;Aromatase inhibitor;Bcl-2;cyclin D1;AR;cell proliferation
出版社: 生命科學系所
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乳癌 (Breast cancer) 由乳房細胞異常增生所造成,為女性最容易罹患的癌症,根據美國癌症協會的統計資料顯示,乳癌在女性癌症致死率排名第二位僅次於肺癌。雌激素 (Estrogen) 與雌激素受體 (Estrogen receptor, ER),對於乳癌的生長 (Proliferation) 與發展 (Development) 扮演重要的角色。因此,針對雌激素作為一個攻擊的目標,將有助於治療乳癌。Anastrozole (ArimidexTM) 屬於芳香酶抑制劑 (Aromatase inhibitor) 的一類,透過抑制芳香酶 (Aromatase) 的活性阻斷雄激素 (Androgen) 轉換為雌激素,進而導致雌激素的濃度下降與雄激素的累積。臨床實驗顯示,乳癌患者給予芳香酶抑制劑 (Exemestens) 治療後,會使腫瘤內的雄激素增加。此外許多文獻顯示,雄激素在乳癌細胞中扮演抑制的角色,可透過降低抗凋亡蛋白Bcl-2的表現進而促使細胞凋亡 (Apoptosis) 的增加或降低細胞週期 (Cell cycle) 調節蛋白cyclin D1的表現進而影響細胞週期抑制細胞生長。顯示雄激素與雄激素受體 (Androgen receptor) 在芳香酶抑制劑抑制乳癌生長中可能扮演重要的角色。因此,本論文研究目的在於探討雄激素與其受體在芳香酶抑制劑 (Anastrozole) 抑制乳癌細胞生長的反應中扮演的角色。研究結果發現,Anastrozole能夠抑制ER+ (Estrogen receptor positive) T-47D、MCF-7 乳癌細胞生長,對於ER- (Estrogen receptor negative) MDA-MB-231、MDA-MB-453、HS578T無影響。同時利用,人工合成雄激素R1881模擬雄激素累積,也能抑制T-47D細胞的生長。進一步實驗發現,Anastrozole能促進T-47D中雄激素 (Testosterone) 濃度上升,也能使AR 與p-S81-AR蛋白質表現增加。同時,Anastrozole也能增加AR進入細胞核中並增加其轉錄活性。此外藉由AR的拮抗劑Casodex阻斷AR,具有逆轉Anastrozole抑制T-47D細胞生長的作用。透過上述研究結果,證實Anastrozole抑制T-47D乳癌細胞生長是透過增加AR蛋白質的表現與活化。進一步我們發現Anastrozole能降低細胞週期調節蛋白cyclin D1表現使細胞週期停滯於G0/G1期,同時也能降低抗凋亡蛋白Bcl-2的表現促使細胞凋亡的發生,進而抑制T-47D細胞生長。綜合上述研究成果,我們發現一個芳香酶抑制劑治療乳癌的新機制,Anastrozole可透過促進AR的表現與活化,同時也能誘導細胞週期停滯於G0/G1期與誘發細胞凋亡,進而抑制乳癌細胞生長。經由以上研究結果,希望這個發現對於未來乳癌的診斷與治療有所貢獻。

Breast cancer is the most prevalent cancer in women. The statistical information from the American Cancer Society indicates that breast cancer is the second leading cause of death in all cancers among women. Estrogen and estrogen receptor play important roles in the growth and development of breast cancer. Therefore, targeting estrogen production is a useful strategy to treat breast cancer. Anastrozole is one type of aromatase inhibitors which can inhibit the conversion of androgen to estrogen. Therefore, the level of estrogen drops and that of androgen accumulates. According to clinical evidence, aromatase inhibitor (Exemestane) could increase intratumoral androgen in human breast carcinoma. Several lines of evidence indicate that androgen exerts a direct inhibitory effect on the proliferation through down-regulating the expression of the anti-apoptotic protein Bcl-2 or cell cycle regulated protein cyclin D1 in human breast cancer cells. It suggests that androgen and its receptor play an important role in inhibiting proliferation of breast cancer cells by aromatase inhibition. Our hypothesis is that androgen might be accumulated after Anastrozole treatment and decreased proliferation of breast cancer cells. Our results show that Anastrozole decreased cell proliferation of estrogen receptor positive T-47D cells and MCF-7 cells, but not estrogen receptor negative MDA-MB-231, MDA-MB-453, and HS578T cells. Administration of synthetic androgen R1881 to mimic androgen accumulation also decreased the proliferation of T-47D cells. In addition, we found that Anastrozole increased cellular testosterone levels of T-47D cells and the levels of androgen receptor protein and S81 phosphorylation were increased. Anastrozole promoted AR translocation into the nucleus of T-47D cells evaluating by fractionation of cellular proteins and immunofluorescent staining, and AR transcription activity was subsequently increased. Moreover, Casodex (AR inhibitor) can reverse Anastrozole-suppressed proliferation of T-47D cells. Altogether, our results indicate that Anastrozole might inhibit T-47D cell proliferation through increasing AR transactivation. Furthermore, Anastrozole decreased the expression of cell cycle regulated protein cyclin D1and cell cycle of T47D was arrested in G1 phase detected by flow cytometry. On the other hand, Anastrozole also decreased the expression of anti-apoptotic protein Bcl-2 and apoptosis of T47D cells was increased which was evaluated by TUNEL assay. In conclusion, our data indicate that Anastrozole might inhibit proliferation of breast cancer cells through AR activation. This finding provides a new mechanism by which aromatase inhibitor reduces breast cancer cell growth. We hope these findings can contribute to diagnosis and treatment of breast cancer in the future.
其他識別: U0005-2407201310451600
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