儘管荷爾蒙療法，標靶療法和化學療法已被證實對於各種不同乳癌亞型（管狀A/B，HER2擴增型，類基底細胞型/緊密連接蛋白低表達型）具有療效，但目前的乳癌治療方式仍有一些限制與副作用。因此，開發針對不同類型乳癌的新策略是重要的。

存活素（BIRC5）是抗凋亡蛋白家族(IAPs)之一員。在分子層次上，存活素可通過直接/間接的方式與半胱氨酸蛋白酶（caspase）結合進而抑制細胞凋亡，並且也可以在細胞中形成染色體載體複合物(chromosomal passenger complex)以促進有絲分裂。然而，與其他IAP家族成員不同的是，存活素主要在胚胎發育過程的胚胎細胞中表達，但並不在已分化的正常組織中表達。有趣的是，存活素在不同類型的癌細胞中具有高度表達的情形並已證實高表達的存活素會促進腫瘤發生與腫瘤轉移，使得這個分子有希望成為治療癌症的標靶分子。

Sepantromium bromide (YM155) 是存活素蛋白的小分子抑制劑。儘管YM155已經達到第I/II期臨床試驗，但其分子作用機轉仍然不明確。YM155是否適用於治療不同的乳癌亞型(包括不同類型的抗藥亞型)仍然不清楚。在我們的初步研究顯示YM155在雌激素受體陽性，管狀A型的MCF-7乳癌細胞中和MCF-7 衍生出的抗泰莫西芬，雌激素非依賴性的乳癌細胞中同樣有效。此外，YM155也可以低納摩爾濃度有效的標定三陰性，緊密連接蛋白低表達型的MDA-MB-231細胞。然而，YM155在乳癌中的詳細分子機轉仍未清楚。本研究主要目的是要探討YM155在不同類型的乳癌細胞中所誘發之細胞死亡的詳細機轉。

在這項研究中，儘管存活素很少被證實能夠調控細胞自噬作用，我們發現使用YM155和小分子干擾核醣核酸抑制存活素的表達時，在人類乳癌細胞MCF-7 (半胱天東酶缺乏型)，MDA-MB-231 (半胱天東酶酶表現型)和SK-Br-3 (HER2，半胱天東酶酶表現型)中會促使自噬作用的發生，並且也會誘導自噬依賴性，但不依賴半胱氨酸蛋白酶的細胞死亡。儘管自噬作用的上調已被廣泛的證明可以促進癌細胞中DNA的修復以應付不同種類的DNA損傷劑，令人驚訝的是，我們發現YM155和存活素的小分子干擾核醣核酸在所有的檢測的乳癌亞型中會誘導早期的自噬依賴性ROS 產生/積累，並且也會導致自噬-ROS依賴性的DNA 損傷。除此之外，通過與ROS抑制劑Tiron共同治療時部分減弱了YM155所誘導的自噬作用，表明可能存在“自噬-ROS-自噬”正回饋迴路，並且可以通過YM155和存活素的小分子干擾核醣核酸在乳癌細胞中激活。有趣的是，在乳癌細胞中，YM155的長時間治療和存活素的小分子干擾核醣核酸會降低各種DNA雙股斷裂修復蛋白，包括Mre11，Rad51和Rad54L在蛋白和基因轉錄的表達。回溯性統計分析進一步揭示了在不同的資料庫中，在正常乳腺組織和乳腺腫瘤組織中，存活素，Rad51和Rad54L之間的表達呈正相關。在本次的研究結果表明，YM155會部分透過上調自噬依賴-ROS 產生/積累和干擾同源性DNA修復過程進而誘導DNA損傷和乳癌細胞死亡。目前的研究結果也顯示存活素可能在癌細胞中存在著尚未發現的自噬作用調節/DNA完整性維護的功能。

Despite hormone therapy, targeted therapy and chemotherapy have been shown to be effective in targeting different breast cancer subtypes (luminal A/B, HER2-enriched, basal/claudin-low), the current breast cancer treatment still have several limitations and undesired side-effects. Thus, it is important to develop novel strategies to target different types of breast cancer.

Survivin (BIRC5) is a member of the inhibitor-of-apoptosis proteins (IAPs) family. At the molecular level, it inhibits apoptosis through direct/indirect caspases-inhibition and promotes mitosis through formation of chromosomal passenger complex in cells. However, unlike other members of the IAPs family, survivin is mainly expressed in embryonic cells during fetal development, but not in the differentiated normal tissues, under physiological conditions. Interestingly, survivin in highly expressed in different cancer cell types and overexpression has widely been demonstrated to promote tumorigenesis and tumor metastasis, making this molecule a promising molecular target for cancer therapy.

Sepantromium bromide (YM155) is a small molecule expression suppressant of survivin. Despite YM155 has reached phase I/II clinical studies, its molecular mechanism of action is still remains unclear. Regarding to breast cancer, it is also unclear on whether YM155 is applicable for treating different breast cancer subtypes (including different drug-resistance subtypes). Our preliminary study revealed that YM155 is equally effective in targeting the estrogen receptor positive (ER+), luminal A-like, MCF-7 breast cancer cells and the MCF-7 derived tamoxifen-resistant, estrogen-independent, breast cancer cells in vitro. It is also effective in targeting the triple-negative, claudin-low-like, MDA-MB-231 cells at low nano-molar concentrations. However, the detail molecular mechanism of action of YM155 on breast cancers remains unclear. The main purpose of this study is to determine the detail mechanism (or differential mechanisms) of action of YM155 in inducing the death of different breast cancer cells.

In this study, despite survivin has seldom been demonstrated to be capable of regulating cell autophagy, we found that YM155 and downregulation of survivin by siRNA both upregulated autophagy and induced autophagy-dependent, but caspase-independent, cell death in human breast MCF-7 (caspase-3 deficient), MDA-MB-231 (caspase-3 expressing), and SK-Br-3 (HER-2 enriched, caspase-3 expressing) cancer cells. Even though upregulation of autophagy has widely been demonstrated to promote DNA repair in cancer cells in response to different DNA damaging agents, surprisingly, we observed that YM155 and survivin siRNA induced early autophagy-dependent ROS production/accumulation and the autophagic-ROS-dependent DNA damage in all of the examined breast cancer subtypes. Moreover, ROS scavenging by co-incubation with Tiron partially attenuated YM155-induced autophagy, suggesting that an “autophagy-ROS-autophagy” positive feedback loop may be exist and can be activated by YM155 and survivin siRNA in breast cancer cells. Interestingly, prolonged YM155 treatment and survivin siRNA also decreased the expression of various DNA double strand break repair proteins including Mre11, Rad51 and Rad54L at both the protein expression and the gene transcription levels in breast cancer cells. Retrospective statistical analysis further revealed that a positive correlation in the expression between survivin, Rad51, and Rad54L in normal breast tissues and breast tumor tissues in different cohorts. In conclusion, findings of this study reveal that YM155 induces DNA damage and breast cancer cell death in part through upregulation of the autophagic-ROS production/accumulation and interferes with the homologous DNA repair process. Findings of the current study also suggest that survivin may exhibit a yet-to-be discovered autophagic regulating/DNA integrity maintaining function in cancer cells.

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