現今對不同種類的乳癌治療方法有許多，包括有賀爾蒙療法、標靶治療或化學藥物治療等，但目前的治療方式仍有許多限制與副作用。因此急需開發另一種治療乳癌的新穎藥物。存活素(survivin)是抗凋亡蛋白家族之一員，且被證實在乳癌的進程中扮演很重要的角色。YM155為一種新穎的存活素小分子抑制劑。雖然已經有許多不同的YM155第二期臨床試驗正在進行，其中也包含在乳癌病患的研究，但對於陽性雌激素受體(ER)-他莫西芬(Tamoxifen)抗藥性之乳癌細胞中，YM155其藥效鮮少被探討，而且YM155在不同乳癌細胞亞型的不同抗癌作用仍舊未明。因此在本篇研究欲探討YM155對於不同種類乳癌的藥效並了解其分子機制。在本研究之細胞實驗中，YM155對於陽性雌激素受體-他莫西芬敏感性之MCF7乳癌細胞，及經由MCF7衍生出之陽性雌激素受體-抗他莫西芬抗藥性之乳癌細胞皆有療效，且在轉移性極強之三陰性(ER-, PR-, HER2-)乳癌細胞MDA-MB-231中也具有抑制生長的效果。過去文獻中普遍認為存活素透過半胱天東脢 (caspase-3)抑制細胞凋零(apoptosis)，而在本篇研究中的西方墨點法、免疫螢光反應以及細胞自噬(autophagy)／細胞凋零抑制實驗中，在大多數測試的細胞（除了TamC3之外）都顯示YM155會增加自噬作用造成細胞死亡，並非透過半胱天東脢依賴性的細胞凋零。此外，在我們測試的細胞中發現到YM155會產生細胞自噬依賴性的DNA損傷。總結以上，本研究顯示在乳癌細胞中利用YM155針對存活素抑制，會增加細胞自噬作用而造成細胞死亡。因此，YM155有潛力及發展價值成為治療不同種類乳癌的抗癌物質。

Despite hormone therapy, targeted therapy and chemotherapy have been developed to target different types of breast cancer; the current breast cancer treatments still have several limitations and undesired side-effects. Thus, it is important to develop novel strategies to treat breast cancer. Survivin (BIRC5) is a member of the inhibitor-of-apoptosis proteins family, and it has been shown to play important role in breast cancer development and progression. YM155 is a novel small molecule inhibitor of survivin. Despite YM155 is currently undergoing different phase II clinical trials including studies in patients with breast cancer, its effectiveness in targeting the estrogen receptor (ER) positive Tamoxifen-resistant breast cancer was seldom determined in the past. In addition, it is still unclear whether YM155 exhibits differential anti-breast cancer functions in different breast cancer subtypes. The purpose of this study is to determine the effectiveness of YM155 in targeting various types of breast cancer and its differential molecular mechanism of action in different breast cancer cell lines. Here, YM155 is equally effective in targeting both the parental ER-positive Tamoxifen-sensitive MCF7 and the MCF7-dervided ER-positive Tamoxifen-resistant breast cancer cells in vitro. YM155 is also effective in targeting the triple-negative MDA-MB-231 breast cancer cells. Surprisingly, Western blot analysis, immunofluorescent microscopy and autophagy/apoptosis inhibition assay revealed that targeting survivin by YM155 induced autophagic cell death, but not caspase-3 dependent apoptosis, in most of the tested breast cancer cell lines; despite it is widely believed that survivin inhibits apoptosis through physical interactions with caspase-3. Interestingly, YM155 also induced autophagy-dependent DNA damage in the treated breast cancer cells. Taken together, targeting survivin by YM155 induces autophagic cell death in breast cancer cells. Importantly, YM155 is a promising anti-cancer compound that has potential for the management of various types of breast cancer.

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