- 學位論文
分裂素原蛋白激酶磷酸酶-1 在乳癌作為預後因子及選擇治療策略中可能扮演的角色
The potential role of MKP-1 for prognosis prediction and therapeutic strategy selection in breast cancer
摘要
分裂素原蛋白激酶 (Mitogen activated protein kinase ,MAPK) 的訊息傳遞路徑調控真核細胞裡廣泛的生理活性。然而，許多報告亦指出 MAPK 活性的改變和人類惡性腫瘤有所關聯，其中亦包括乳癌。分裂素原蛋白激酶磷酸酶-1 (MAPK phosphatase-1, MKP-1) 為一種可將 MAPK 去磷酸化的酥胺酸 (threonine) 及酪胺酸 (tyrosine) 雙重特異性去磷酸酶。因此，MKP-1 表現量的改變可能在乳癌也佔有很重要的地位。在本次的研究中，我們探討 MKP-1 的變化在乳癌中可能扮演的角色。免疫點漬法分析結果顯示 MKP-1 和雌激素受體的表現狀態有關 (p = 0.141)，並且 MKP-1 蛋白質表現量的增加可改善乳癌病患的存活率 (p = 0.008)。此外，免疫組織化學染色及甲基化特異性聚合酶連鎖反應 (methylation-specific PCR) 結果皆顯示MKP-1的表現量與乳癌的復發呈現負相關 (p = 0.031、p = 0.004 及 p = 0.029)。有趣的是，雌激素受體陽性的乳癌細胞株 MCF-7 經過 tamoxifen 處理後其 MKP-1 表現量會快速的增加，但在雌激素受體陰性的乳癌細胞株 MDA-MB-231 則不會有相同的現象產生。因此，MKP-1可能在乳癌中扮演腫瘤抑制的角色，並且，可能參與 tamoxifen 行使雌激素受體依賴路徑執行抗癌活性的過程。我們的研究結果將可提供臨床醫生選擇治療策略及預後因子上一個新的觀點。
並列摘要
Mitogen activated protein kinase (MAPK) signaling is widespread in modulating multiple physical activities of eukaryotic cell. However, numerous reports have also demonstrated that aberrant activation of MAPK signaling is associated with human malignancies including breast cancer. MKP-1 is one of the threonine-tyrosine dual-specificity phosphatases that have been shown to dephosphorylate and thereby inactivate MAPKs. Thus, it is presumably possible that alterations of MKP-1 may play some roles in breast cancer. In this study, we explore the potential role of MKP-1 alternation in breast cancer. Immunoblotting results showed that MKP-1 was associated with ER status (p = 0.141) and an increased MKP-1 protein could improve overall survival rate of the patients (p = 0.008). Furthermore, both immunohistochemical staining and methylation-specific PCR results were negatively correlated with a positive recurrence rate (p = 0.031, p = 0.004, p = 0.029). Moreover, tamoxifen treatment rapidly increased MKP-1 levels in ER-positive MCF-7 cells but not in ER-negative MDA-MB-231 cells. Herein, our results provide a new insight for selecting therapeutic strategy and novel prognostic predictor. MKP-1 may serve as a tumor suppressor and contribute to a part of anti-cancer activities of tamoxifen via an ER-dependent manner in breast cancer.