Abstract 3452: YM155 induces autophagy-dependent cell death in Tamoxifen-resistant breast cancer cells.

Abstract

Typically, patients with estrogen receptor positive (ER-positive) breast tumors will receive Tamoxifen either as a first line treatment or as a second line treatment after surgery. Despite the benefit of using Tamoxifen as hormonal therapy in treating ER-positive breast cancers has been widely demonstrated in patients at early treatment stages, its effectiveness seems to be significantly reduced in patients after five years post-treatment. Interestingly, two thirds of the tumors that become resistant to Tamoxifen continue to express ER. Thus, it is necessary to develop novel strategies that can be applied to target ER-positive Tamoxifen-resistant breast cancer cells. On the other hand, it is also in urgent to develop novel agents that can be used to target triple-negative metastatic aggressive breast cancers, given that current therapeutic selection for this cancer is still limited. Survivin is a member of the inhibitor-of-apoptosis proteins family. It has been shown that expression of survivin is positively correlated to the breast cancer progression and inversely correlated to the survival period of patient after chemotherapeutic/hormonal treatments. YM155 is a small molecule survivin gene suppressant. Although the functionality of YM155 in targeting lymphoma and lung cancer cells has been shown in vitro and in vivo, and the pharmacokinetics and the maximum tolerance dose of YM155 have also been evaluated in patients with non-Hodgkin's lymphoma and non-small cell lung cancer, its effectiveness in targeting ER-positive Tamoxifen resistant breast cancers and triple-negative metastatic aggressive breast cancers has not yet been determined. Furthermore, the detailed molecular mechanism of actions of YM155 is still unclear. In this study, the effectiveness of YM155 in targeting a series of newly-generated MCF7-derivded ER-positive Tamoxifen-resistant breast cancers (TamR7, TamR8, TamC3 and TamC6) and the triple-negative Tamoxifen-resistant MDA-MB-231 breast cancer cells has been determined. MTT cell viability assay revealed that YM155 is equally effective in targeting both the parental MCF7 and MCF7-derivded Tamoxifen-resistant breast cancer cells in vitro. YM155 is also effective in targeting the triple-negative MDA-MB-231 breast cancer cells with an IC50 value in low nanomolar range. Interestingly, Western blot analysis and MTT assay (3MA or Z-VAD-FMK co-treated) revealed that YM155 induces autophagy-dependent cell death, but not caspase-3 dependent apoptosis, in the treated cancer cells, despite it is widely believed that survivin can functionally inhibit apoptosis through caspase-3 inhibition. In addition, YM155 also induces the expression of gamma H2AX, indicating the induction of DNA damage in the treated breast cancer cells. In conclusion, YM155 is effective in targeting various types of Tamoxifen-resistant breast cancers through induction of autophagy-dependent cell death. Citation Format: Chih-Yun Liu, Siao Muk Cheng, Euphemia Leung, Chun Hei Antonio Cheung. YM155 induces autophagy-dependent cell death in Tamoxifen-resistant breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3452. doi:10.1158/1538-7445.AM2013-3452