Shikonin reduces tamoxifen resistance through long non-coding RNA uc.57.

Chen-Han Zhang,Jue Wang,Lu Xu,Yi-Han Lu,Li-Jun Ling,Lin-Xin Zhang,Tian-Hao Ji

doi:10.18632/oncotarget.20809

Abstract

Tamoxifen resistance is a serious problem in the endocrine therapy of breast cancer. Long non-coding RNAs play important roles in tumor development. In this study, we revealed the involvement of lncRNA uc.57 and its downstream gene BCL11A in TAM resistance. Tamoxifen-resistant MCF-7R cells showed lower expression of uc.57 and higher expression of BCL11A mRNA and protein than the parental MCF-7 cells. Moreover, levels of uc.57 mRNA were lower and BCL11A mRNA were higher in breast cancer tissues than in precancerous breast tissues. Shikonin treatment reduced tamoxifen resistance in MCF-7R cells both in vitro and in vivo, targeting uc.57/BCL11A. Fluorescence in situ hybridization and RNA immunoprecipitation analyses showed that uc.57 binds to BCL11A. Uc.57 overexpression downregulated BCL11A and reduced tamoxifen resistance in MCF-7R cells both in vitro and in vivo. BCL11A knockdown also reduced tamoxifen resistance by inhibiting PI3K/AKT and MAPK signaling pathways. It thus appears shikonin reduces tamoxifen resistance of MCF-7R breast cancer cells by inducing uc.57, which downregulates BCL11A to inhibit PI3K/AKT and MAPK signaling pathways.

Highlights

Breast cancer is the most common malignancy and second leading cause of cancer-related deaths in women worldwide [1]
Uc.57 expression was lower in breast cancer tissues than in precancerous tissues (Figure 1B)
This suggested that low uc.57 levels were linked to TAM resistance in breast cancer cells

Summary

Introduction

Breast cancer is the most common malignancy and second leading cause of cancer-related deaths in women worldwide [1]. Shikonin (SK) is an active ingredient isolated from the Chinese herb, Lithospermum erythrorhizon, which has been used for thousands of years in traditional Chinese medicine It exerts anti-inflammatory [4], wound healing [5], and anti-cancer [6, 7] effects. SK inhibits estrogen-dependent tumor cell growth and promotes the anti-estrogen effect of endocrine therapy in breast cancer [8, 9] It modulates mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways to suppress growth and survival of the malignant tumor cells [7, 10]. MAPK and PI3K pathways are critical players in TAM resistance [11,12,13] and their inhibition promotes TAM sensitivity [14,15,16] This suggests that SK would be therapeutically beneficial to reduce TAM resistance in breast cancer cells

Methods

Results

Conclusion