臺灣博碩士論文加值系統

臺灣乳癌的發生率在過去二十年中，可能導因於西化的生活方式而有迅速增加的趨勢；然而，臺灣的乳癌族群似乎遠較西方的乳癌族群具有較低的發生率以及早發的年齡，這些差異暗示造成臺灣乳癌發生的機轉可能不同於西方乳癌的發生。
轉錄訊息傳遞及活化子蛋白(Signal Transducer and Activator of Transcription，STAT)是一群包括STAT1，2，3，4，5A，5B及6在內的轉錄因子家族。在這些轉錄因子之中，STAT3是唯一被認為隱含於胚胎的早期死亡的成員。也因此STAT3經常被認定是一個潛在性的致癌基因。雖然絕大多數的人類腫瘤細胞株以及初級腫瘤上常可發現在酪胺酸705位置上持續磷酸化的活化型STAT3。證據顯示STAT3也參與了泌乳後乳腺退化期中上皮細胞的凋亡過程。或許大部分的機制仍未趨於明朗；但是，這樣矛盾的現象似乎引申出了一個有趣的課題：爲什麼像STAT3這樣的單一轉錄因子卻能操控兩種幾乎完全相互矛盾的細胞反應。
為了探索STAT3訊息傳遞是否參與臺灣乳癌的發展，本論文以免疫點漬及免疫組織染色的方法分析他們在成對的乳癌(C)以及鄰近非癌(N)乳房組織上的表現。結果顯示：p-tyr705-STAT3a 在68.9%的乳癌組織中表現量下降(C<N)，並且與增加的腫瘤未分化等級以及淋巴結未轉移的乳癌患者的較佳存活率有關(p=0.009及0.021)。同時，p-ser727-STAT3在68.1%的乳癌組織上表現量顯著增加(C>N)，並與增加的腫瘤階段、腫瘤大小以及活體內、外陰性的雌激素受體表現狀態有所關聯(p=0.001，0.024及0.014)。此外，48.5%的乳癌組織中p-JNK1/2的表現量下降且與腫瘤未分化等級的增加、被診斷出乳癌之年齡的減少及較佳的存活率顯著相關(p=0.030，0.029及0.004)。多維性考克斯回歸分析(multivariate COX regression analysis)顯示p-ser727-STAT3及p-JNK1/2的表現形式對臺灣乳癌病人之整體存活率而言，為兩個有效的風險決定因子(p=0.030及0.007)。因此總結本論文的結果可得知STAT3訊息傳遞成員的磷酸化表型的改變可能在臺灣乳癌的發生扮演了某些特定的角色。

Although the incidence of Taiwanese breast cancer is rapidly increased compared to the past 2 decades, possibly resulted from the westernized life style, the lower incidence and earlier onset of Taiwanese breast cancer than those of Western breast cancer implicate that other mechanisms contributing to Western breast cancer may play roles in the development of Taiwanese breast cancer.
Signal transducers and activators of transcription (STATs) proteins are a group of transcription factors including STAT1, 2, 3, 4, 5A, 5B, and 6. Among them, STAT 3 is frequently regarded as an oncogene originally due to its involvement in early embryonic lethality. Constitutive STAT3 activation, through tyrosine phosphorylation at Y705, has been demonstrated in a wide range of human cancer cells and primary tumors. However, STAT3 is also involved in the involution, an apoptotic process of epithelial cells of the post-lactating mammary gland. Although the underlying mechanism is mostly unclear, it raises an interesting issue how a single transcription factor can be involved in the seemingly contradictory cell responses.
To explore whether STAT3 signaling participates the development of Taiwanese breast cancer, their immunoblotting and immunohistochemical expressions in the paired cancer (C) and non-cancer (N) breast tissues were analyzed in this study. The results showed that decreased p-tyr705-STAT3a expression in 68.9% of breast cancer tissues (C<N) was positively correlated with tumor grade and better survival of node-negative breast cancer cases (p=0.09 and 0.021), while elevated p-ser727-STAT3 expression in 68.9% of breast cancer tissues (C>N) was correlated with increased tumor stage and size (p=0.024 and 0.014), and negative estrogen receptor status in vivo (p=0.001) and in vitro. In addition, the expression of p-JNK decreased in 68.9% of breast cancer tissues (C<N) and was correlated with increased tumor grade, decreased age at diagnosis, and better overall survival (p=0.030, 0.029, and 0.004). Eventually, multivariate COX regression analysis showed that both p-ser727-STAT3 and p-JNK1/2 were risk determinants for Taiwanese breast cancer (p=0.030 and 0.007). In conclusion, our results indicate that alternations of phosphorylated forms of STAT3 signaling members may play roles in Taiwanese breast cancer.

總緒論
第一節、轉錄訊息傳遞及活化子(signal transducers and activators of transcription，STATs)家族 1
第二節、轉錄訊息傳遞及活化子3 (signal transducer and activator of transcription 3，STAT3)在癌化過程中可能扮演的角色 4
第三節、研究目的與實驗構想 7

第一部分：酪胺酸705磷酸化的STAT3a (p-tyr705-STAT3a)及其異構體STAT3b (p-tyr705-STAT3b)在乳癌所扮演的角色以及可能具有的預斷價值
中文摘要 11
英文摘要 12
實驗背景及研究目的 14
研究方法與材料 17
實驗結果 20
討論 22
附表及附圖 25

第二部分：絲胺酸727磷酸化的STAT3 (p-ser727-STAT3)在乳癌所扮演的角色
中文摘要 32
英文摘要 33
實驗背景及研究目的 34
研究方法與材料 37
實驗結果 40
討論 43
附表及附圖 46

第三部分：磷酸化c-jun NH2-terminal kinase (p-JNK)以及MAPK家族成員之交互作用在乳癌所扮演的角色
中文摘要 52
英文摘要 53
實驗背景及研究目的 54
研究方法與材料 56
實驗結果 59
討論 61
附表及附圖 64

總結論及討論 74
參考文獻 79
附錄
附表及附圖 94
研究著作 99

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