臺灣博碩士論文加值系統

近年來乳癌病患在接受荷爾蒙治療(如Tamoxifen, aromatase inhibitors)或標靶治療(如Tratuzumab)時，尋求中醫藥的輔助治療有持續增加的趨勢。之前本實驗室研究發現，四物湯在體外細胞模式(MCF-7 細胞株)能促進乳癌細胞增殖，其機轉乃經由活化HER2及其下游ERK，AKT之訊息傳遞，進而提高由ER調控的細胞增殖相關的PS2，ESR1及HER2基因表現。另外從全民健康保險資料庫分析，乳癌病患尋求中醫輔助治療最常使用的處方為加味逍遙散，本研究目的為探討中藥常用方劑中四物湯及加味逍遙散對人類乳癌細胞株合併使用Tamoxifen或Trastuzumab之活體及體外研究。

研究方法在活體模式使用8週的雌性BALB/c 裸鼠，分為對照組、雌激素組、Tamoxifen組、四物湯組、四物湯加Tamoxifen組、加味逍遙散(1.3g /kg)加Tamoxifen組、加味逍遙散(2.6g /kg)加Tamoxifen組、加味逍遙散(3.9g /kg)加Tamoxifen組，於餵食21天後犧牲，測量體重、子宮重量、腫瘤重量、腫瘤體積，並將取下組織做病理切片染色、免疫組織染色及西方點墨法(Western blot)，探討信息傳遞。在體外模式以三種人類乳癌細胞株MCF-7(有estrogen receptor(ER)，低HER2表現)、 SK-BR-3(無ER，高HER2表現)及BT-474(有ER，高HER2表現)為研究模式。用MTT assay及流式細胞儀分析四物湯及加味逍遙散之細胞增殖作用，進一步以西方點墨法，免疫螢光染色法及螢光報導基因分析(Luciferase reporter assay)探討信息傳遞及基因表現之變化。

結果顯示四物湯加Tamoxifen可以促進MCF-7乳癌細胞株增生，使裸鼠腫瘤重
量、腫瘤體積增加，以及ERα和N-cadherin的表現增強。在HER2(+)細胞株(SK-BR-3和BT-474)，四物湯可以逆轉Trastuzumab抗腫瘤細胞增殖的效果，其機轉是透過促進細胞週期調控蛋白質P27(Kip1)的磷酸化，或可能是調控抗細胞凋亡的蛋白質P38。在加味逍遙散的部分其與Tamoxifen的藥物交互影響，在體外及活體研究都無統計學上有顯著意義的改變，除了在活體研究會影響LC3II蛋白質的表現。

本研究結論中醫或西醫在治療受體陽性(如ER (+)或PR(+)或HER2 (+))的乳癌病人，如果有合併使用輔助中藥治療時，應特別注意中西藥可能產生之藥物交互影響。同時提供中西醫師在治療乳癌病患合併中西藥使用時，藥物交互作用的重要資訊。

There is recent trend whereby patients with breast cancer seek integrative medical treatment when receiving either hormonal (tamoxifen) or target (trastuzumab) therapies. Our previous in vitro studies demonstrated that the Chinese medicine Si-Wu-Tang (SWT) stimulates MCF-7 cell growth via activation of ER-α and HER-2 signaling. Traditional Chinese medicine (TCM), one of the most commonly used complementary and alternative medicine (CAM) in Taiwan, has been increasingly used to treat breast cancer when receiving hormonal (tamoxifen) therapies recently. Jia-Wei-Xiao-Yao-San (JWXYS) was the most common Traditional Chinese medicine used in all prescriptions from the National Health Insurance Research Database of Taiwan. The present study was aimed to investigate herb-drug interaction of cell proliferation in tumor-bearing mice (in vivo) treated with SWT and tamoxifen and such interaction of proliferation capacity in breast cancer cells treated with SWT and trastuzumab in vitro and in vitro and in vitro evidence of interaction between JWXYS and tamoxifen.

To assess in vivo SWT-Tamoxifen interaction, female MCF-7 implanted athymic nude mice were randomly separated into five groups, namely, vehicle, estradiol, SWT, tamoxifen and SWT + Tamoxifen groups. All mice were sacrificed after 21 days of treatment. Body weight, uterine weight, tumor volume and tumor weight were measured. To assess in vitro SWT-trastuzumab interaction, BT-474 and SK-BR-3 breast cancer cells were co-treated with SWT and trastuzumab. This was followed by MTT assays and cell cycle analysis to measure cell proliferation and Western blotting to analyze the protein expression in growth-related signal pathways.

To assess JWXYS + Tamoxifen interaction, MCF-7 breast cancer cells were co-treated with JWXYS and Tamoxifen. This was followed by MTT assays and cell cycle analysis to measure cell proliferation and Western blotting to analyze the protein expression in growth-related signal pathways. Immunohistochemistry was performed to detecting autophage in cancer cells.To assess JWXYS-Tamoxifen interaction, female MCF-7 implanted athymic nude mice were randomly separated into six groups, namely, vehicle, estrodial, Tamoxifen , JWXYS(1.3 g /kg) + Tamoxifen, JWXYS(2.6 g /kg) + Tamoxifen, JWXYS(3.9 g/kg) + Tamoxifen groups. All mice were sacrificed after 21 days of treatment. Body weight, tumor volume and tumor weight were measured.

SWT reversed tamoxifen-induced anti-proliferative effects such as tumor weight, tumor volume and increased ER-α and N-cadherin expression among the SWT + Tamoxifen-treated group, compared to Tamoxifen-treated group. Furthermore, SWT reversed trastuzumab-induced anti-proliferative activity in HER2 (+) cell lines (SK-BR-3 and BT-474) through increased phosphorylation of the cell cycle regulatory protein p27(Kip1) and possibly the anti-apoptosis protein P38.

The results showed that JWXYS had no cytotoxicity on MCF-7 cells. There were no statistical changes, in terms of cell number, cell cycles, proliferation signals such as AKT, ERK, P38, p27(Kip1), and LC3II expression between JWXYS + Tamoxifen groups and Tamoxifen alone group. Besides, in MCF-7 xenograft mice, there was no significant changes, in terms of tumor weight, the protein expression of AKT, ERK, P38 and p27(Kip1), between JWXYS (1.3 ~ 3.9 g/kg) + Tamoxifen groups and Tamoxifen alone group. However, there was a significantly decreased LC3II protein expression in low dose (1.3 g/kg), but not middle dose (2.6 g/kg) or high dose (3.9 g/kg), of JWXYS + Tamoxifen groups, compared to Tamoxifen alone group.

Based on the in vivo and in vitro demonstration of herb-drug interference in breast cancer cells, we conclude that physicians should pay more attention to such interference when treating patients with receptors (+) [ ER (+) or PR(+) or HER2 (+) ] breast cancers.

Table of Contents
Signature Page i
Thesis Approval Form ii
Acknowledgments iii
Table of Contents iv
Chinese Abstract vii
English Abstract ix
List of Figures xii
List of Tables xvi
Chapter 1 Introduction:
1.1 The epidemiology of breast cancer…………………………………………...1
1.2 Breast cancer and risk factors………………………………………………...2
1.3 Prognostic factors of breast cancer…………………………………………...2
1.4 Estrogen receptor (ER) and breast cancer…………………………………….4
1.5 HER2 and breast cancer………………………………………………………5
1.6 The conventional treatment for breast cancer………………………………...6
1.7 Traditional Chinese Medicine and breast cancer……………………………..8
1.8 Rationale and aim of study…………………………………………………..14
Chapter 2 Materials and Methods:
2.1 Cell lines and reagents………………………………………………………16
2.2 Preparation of Si-Wu-Tang (SWT) extract…………………………………..16
2.3 Preparation of Jia Wei Xiao Yao San (JWXYS) extract…………………….17
2.4 Study protocol for the in vivo interaction between
SWT and Tamoxifen ………............................................................................18
2.5 Study protocol for the in vivo interaction between
JWXYS and Tamoxifen……………………………………………………...19
2.6 Immunohistochemistry staining for ER expression….................................20
2.7 Immunohistochemistry staining for N-cadherin expression….......................21
2.8 Immunohistochemistry staining for autophage (LC3II) expression………..21
2.9 Assessment of cell proliferation and cytotoxicity…………………………..22
2.10 Cell cycle analysis…………………………………………………………23
2.11 Luciferase reporter assay…………………………………………………..23
2.12 Western blot analysis………………………………………………………24
2.13 Statistical methods………………………………………………………...27
Chapter 3 Results:
3.1 Effects of SWT on tamoxifen-treated MCF-7 implanted athymic
nude mice…………………………………………………………………….28
3.2 Effects of SWT on ERα expression in MCF-7 cells-implanted athymic
nude mice…………………………………………………………………….28
3.3 Effects of SWT on proteins expression in tamoxifen-treated
MCF-7-implanted athymic nude……………………………………………..29
3.4 Effects of SWT on N-cadherin expression in tamoxifen-treated
MCF-7 implanted athymic nude mice………………………………………..29
3.5 Effects of SWT on cell growth and proteins expression in
trastuzumab-treated SK-BR-3 breast cancer cells in vitro…………………...30
3.6 Effects of SWT on cell growth and proteins expression in
trastuzumab-treated BT-474 breast cancer cells in vitro……..........................30
3.7 Effects of JWXYS on cell viability………………………...............................31
3.8 Effects of JWXYS on luciferase reporter assay………………………………31
3.9 Effects of JWXYS on cell growth and proteins expression in
tamoxifen-treated MCF-7 breast cancer cells in vitro………………………...32
3.10 Effects of JWXYS on the signaling pathways in tamoxifen-treated
MCF-7 breast cancer cells in vitro…………………………………………..32
3.11 Herb-drug interaction on tamoxifen induces autophage in MCF-7
breast cancer cells in vitro………………………………………………….32
3.12 Effects of JWXYS on tamoxifen-treated MCF-7 implanted athymic
nude mice…………………………………………………………………….33
3.13 Effects of JWXYS on proteins expression in
tamoxifen-treated MCF-7-implanted athymic nude mice…………………....33
3.14 Effects of JWXYS on LC3II expression in tamoxifen-treated
MCF-7 cells-implanted athymic nude mice………………………………….34
Chapter 4 Discussion:
4.1 Research about SWT…………………………………………………………..35
4.2 Research about JWXYS……………………………………………………….36
4.3 Herb-drug interaction between SWT and tamoxifen in vivo……………….....37
4.4 Herb-drug interaction between SWT and trastuzumab in vitro…………….....38
4.5 Herb-drug interaction between JWXYS and tamoxifen in vitro……………....39
4.6 Herb-drug interaction between JWXYS and tamoxifen in vivo……………....39
4.7 Effects of SWT on p27Kip1 signaling………………………………………....40
4.8 Effects of JWXYS on p27Kip1 signaling……………………………………...41
4.9 Effects of SWT on P38MAPK signaling………………………………………41
4.10 Effects of JWXYS on P38MAPK signaling………………………………….41
4.11 Effects of SWT on the epithelial mesenchymal transition (EMT) and
N-cadherin expression………………………………………………………..42
4.12 Effects of JWXYS on autophage……………………………………………..42
4.13 Herb-drug interference and herb-drug interaction…………………………....43
Chapter 5 Conclusion....................................................................................................48

References………………………………………………………………………….....49

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