Background: Tamoxifen is an antagonist of the estrogen receptor (ER) in breast tissue and has been a standard anti-estrogen agent in hormone receptor-positive breast cancers. Previous studies have indicated that tamoxifen also induces estrogen receptor-independent cell death in ER-negative breast cancer cells. Our previous study has shown that CIP2A, cancerous inhibitor of PP2A, may be a novel target in breast cancer cells (Breast Cancer Research 2012). Here, we tested efficacy of tamoxifen in a panel of ER-negative breast cancer cells and examined the drug mechanism. Methods: ER-negative breast cancer cell lines (HCC-1937, SK-BR3, MDA-MB-468, MDA-MB-453, MDA-MB-231) were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). In vivo efficacy of tamoxifen was tested in nude mice with breast cancer xenografts. Results: Tamoxifen showed differential effects on apoptosis in human ER-negative breast cancer cell lines. Tamoxifen induced significant apoptosis in SK-BR3, MDA-MB-468, MDA-MB-453, MDA-MB-231 cell lines; however, HCC-1937 cells were resistance to tamoxifen-induced apoptosis. Tamoxifen inhibited CIP2A in a dose-dependent manner in all sensitive ER-negative breast cancer cells, but not in resistant cells (HCC-1937). Overexpression of CIP2A protected MDA-MB-231 cells from tamoxifen-induced apoptosis. In addition, silencing CIP2A by siRNA sensitized HCC-1937 cells to tamoxifen-induced apoptosis. Moreover, in vivo xenograft data showed that tamoxifen inhibited the growth of MDA-MB-468 tumors but had no effect on HCC-1937 tumors. Furthermore, tamoxifen downregulated CIP2A in sensitive MDA-MB-468 xenograft tumors, but not in HCC-1937 tumors. Conclusions: Inhibition of CIP2A determines the effects of tamoxifen-induced apoptosis in ER-negative breast cancer cells. (Supported by Yen Tjing Ling Medical Foundation; NSC 101-2325-B-075-006 and NSC 100-2325-B-010-007; and V100-D-005-4)

Citation Format: Ling-Min Tseng, Chun-Yu Liu, Kung-Chi Chang, Duen-Shian Wang, Chung-Wai Shiau, Kuen-Feng Chen. CIP2A mediates the effect of tamoxifen-induced apoptosis in estrogen receptor negative 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 914. doi:10.1158/1538-7445.AM2013-914