臺灣博碩士論文加值系統

乳癌是目前排名第三且好發於女性的癌症。此外，在臨床中，對於陽性雌激素受體、具他莫西芬抗藥性之乳癌以及三陰性乳癌仍有治療上的瓶頸。白藜蘆醇是在葡萄及紅葡萄酒中一個天然的抗氧化物，有趣的是，許多研究指出白藜蘆醇具有廣泛的藥理特性並且具有作為抗癌藥物的潛力。然而，儘管白藜蘆醇抗癌的效果已被廣泛的研究，但其確切的分子作用機制仍然不明。此外，白藜蘆醇對於不同亞型的乳癌患者是否可作為治療藥物目前也未知。

在本研究中，我們發現儘管白藜蘆醇對於管腔A型的MCF7、MCF7衍生出之陽性雌激素受體-抗他莫西芬之MCF7-TamC3、HER2表現型的SK-BR-3以及三陰性的MDA-MB-231乳癌細胞都會抑制細胞的存活。但在體內實驗中發現，白藜蘆醇在不同的乳癌細胞中具有不同的抗增生能力以及不同程度的毒殺能力。從顯微鏡觀察、Brdu細胞生長速率測試、及LDH細胞毒性測試的分析中顯示，用MTT 細胞存活測試得到的兩倍IC50濃度的白藜蘆醇在MCF7及SK-BR-3乳癌細胞中會誘導早期的細胞增生抑制(給藥後24小時)以及細胞死亡(給藥後48小時)。意外的是，兩倍IC50濃度的白藜蘆醇在MDA-MB-231乳癌細胞中則會延緩細胞增生抑制以及細胞死亡。在分子層次，西方墨點法分析指出在MCF7以及SK-BR-3乳癌細胞中，白藜蘆醇會在給藥24小時後增加DNA損傷的標誌- γH2AX的蛋白表現。相反的，在MDA-MB-231乳癌細胞中則是在給藥後48小時後才觀察到γH2AX的蛋白表現有增加的情形。值得注意的是，使用Brdu細胞生長速率測試取代MTT細胞存活測試，重新分析白藜蘆醇在不同細胞中的IC50濃度，結果顯示在MDA-MB-231乳癌細胞中，其測得的IC50濃度比MCF7以及SK-BR-3乳癌細胞測得的濃度高出了至少2倍。這些結果顯示了MDA-MB-231乳癌細胞在體內實驗中比MCF7以及SK-BR-3乳癌細胞更具抗藥性。在分子機制研究中顯示，白藜蘆醇在MCF7, SK-BR-3以及MDA-MB-231乳癌細胞中都會抑制屬於抑制凋亡蛋白家族成員中的IAP-2之蛋白表現，意外的是，白藜蘆醇只會在MCF7以及SK-BR-3乳癌細胞中抑制同屬於抑制凋亡蛋白家族成員中的存活素蛋白表現。事實上，白藜蘆醇在MDA-MB-231乳癌細胞中增加了存活素蛋白的表現以及提高存活素蛋白的穩定性。除此之外，白藜蘆醇在這三種測試的乳癌細胞株中都增加了Bcl-2這個已知的抑制細胞凋亡的蛋白之表現。

綜合上述結果，我們的發現顯示白藜蘆醇在不同的乳癌細胞中有不同的作用效果，而此結果可能是透過存活素不同的調控造成。此外，透過和標靶Bcl-2的合併治療可能可以對白藜蘆醇在臨床應用上所遇到的困難提供一個較佳的選擇，此篇研究結果對於未來在使用白藜蘆醇作為治療藥物時，針對特定的乳癌患者能提供重要的資訊。

Breast cancer ranks the top three cancers with high incidence rate among women. In addition, treating patients with estrogen receptor positive tamoxifen-resistant breast cancer and triple-negative breast cancer remains to be a therapeutic challenge in clinical situations. Resveratrol (3, 5, 4'- trans- trihydroxystilbene) is an anti-oxidant found in grapes and red wine. Interestingly, resveratrol has been shown to exhibit a wide spectrum of pharmacological properties with potential to be an anti-cancer agent. However, despite the anti-cancer effect of resveratrol has already been shown in a few studies, its molecular mechanism of actions are still incompletely known. Furthermore, it is still unclear on whether resveratrol can be used as a therapeutic agent for patients with different breast cancer subtypes.

In this study, we found that despite resveratrol exhibits similar cell viability inhibitory effects on the lumen A-like MCF7, MCF7-derivded tamoxifen-resistant MCF7-TamC3, HER2-like SK-BR-3, and basal-like triple-negative MDA-MB-231 breast cancer cells, it exhibits differential anti-proliferative effects and cytotoxicity towards different breast cancer cells in vitro. Results of the microscopic analysis, Brdu cell proliferation assay and LDH cytotoxicity assay showed that 2xIC50(MTT) (as determined by the MTT assay) resveratrol induced early cell proliferation inhibition (24 h post-treatment) and cell death (48 h post-treatment) in MCF7 and SK-BR-3 cells. Surprisingly, 2xIC50(MTT) resveratrol induced delayed cell proliferation inhibition and cell death in MDA-MB-231 cells. At the molecular level, Western blot analysis revealed that resveratrol increased the expression of gamma H2AX, which is a DNA damage marker, in MCF7 and SK-BR-3 as early as 24 h post-treatment. In contrast, increased expression of gamma H2AX was only observed in MDA-MB-231 cells 48 h post-treatment. Noticeably, re-determination of the IC50 values using the Brdu cell proliferation assay [IC50(Brdu)] instead of the originally used MTT cell viability assay showed that the IC50(Brdu) of resveratrol in MDA-MB-231 cells is at least 2-fold higher than that in MCF7 and SK-BR-3 cells. These results indicate that MDA-MB-231 cells are more resistant to resveratrol than MCF7 and SK-BR-3 cells in vitro. Mechanistic studies revealed that resveratrol decreased the expression of IAP-2, which is a member of the inhibitor-of-apoptosis proteins (IAPs) family, in MCF7, SK-BR-3 and MDA-MB-231 cells. Surprisingly, resveratrol only decreased the expression of survivin in MCF7 and SK-BR-3 cells but not in MDA-MB-231 cells. Indeed, resveratrol increased the expression of survivin and increased the stability of survivin protein in MDA-MB-231 cells. Moreover, resveratrol also up-regulated the expression of Bcl-2, which is a well-known inhibitor of apoptosis, in all of the tested breast cancer cell lines.

Taken together, our findings indicate that resveratrol induced differential cellular effects at least in part through differential regulation of survivin expression in different breast cancer subtypes. In addition, combination of Bcl-2 targeted therapy may provide a better therapeutic option against the odds of resveratrol in clinical application. Results of this study may provide important information for the use of resveratrol as a therapeutic agent for specific breast cancer subpopulations in the future.

中文摘要............................................... II
ABSTRACT............................................... V
誌謝................................................ VIII
Abbreviation.......................................... IX
List of Tables....................................... XII
List of Figures..................................... XIII
List of Appendices.................................... XV
INTRODUCTION........................................... 1
1.1. Breast Cancer..................................... 2
1.1.1. The epidemiology of breast cancer............... 2
1.1.2. Treatments of breast cancer..................... 2
1.1.3. Challenges in breast cancer treatment........... 4
1.2. Resveratrol (3, 5, 4'-trans-trihydroxystilbene)... 4
1.2.1. Biological effects of Resveratrol............... 4
1.2.2. Resveratrol and cancer.......................... 5
1.3. Inhibitor of Apoptosis Proteins (IAPs)................................................. 6
1.3.1. IAP family and cancer........................... 6
1.3.2. Survivin and cancer............................. 7
1.3.3. Functions of survivin........................... 8
1.3.4. Regulation of survivin in cancer................ 9
1.4. Aims of this study............................... 11
MATERIALS AND METHODS................................. 12
2.1. Materials........................................ 13
2.2. Recipes.......................................... 16
2.3. Methods.......................................... 18
2.3.1. Cells and culture.............................. 18
2.3.2. MTT cell viability assay....................... 19
2.3.3. Bromodeoxyuridine (BrdU) cell proliferation assay .......................................................19
2.3.4. Lactate dehydrogenase (LDH) cell cytotoxicity assay ................................................ 20
2.3.5. Comet assay.................................... 20
2.3.6. Western blot analysis.......................... 21
2.3.7. Gene silencing by siRNA........................ 22
2.3.8. Protein stability Assay........................ 22
2.3.9. Gene Set Analysis-Tumor settings............... 23
2.3.10. Statistic analysis............................ 23
RESULTS............................................... 24
3.1. Resveratrol induces differential cellular effects in different breast cancer subtypes.......................25
3.2. Resveratrol induces differential anti-proliferative effects and DNA damages in MCF7, SK-BR-3 and MDA-MB-231 cells................................................. 26
3.3. Resveratrol induces differential molecular effects in MCF7, SK-BR-3 and MDA-MB-231 cells................. 27
3.4. Differential regulation of survivin expression plays an important role in the differential potency of resveratrol exhibited in different breast cancer cells.28
3.5. Resveratrol increases the expression of survivin through mTOR-4E-BP1- and protein stability- independent pathway in MDA-MB-231 cells .................. ........30
3.6. Resveratrol down-regulates the expression of HDAC2 in breast cancer cells................................ 30
DISCUSSION ＆.......................................... 32
CONCLUSIONS........................................... 32
4.1. Discussion....................................... 33
4.2. Conclusions...................................... 36
REFERENCES............................................ 37
TABLES................................................ 50
FIGURES............................................... 55
APPENDICES............................................ 69

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