Blocking the formation of radiation-induced breast cancer stem cells.

Yangyang Wang,Elena F Brachtel,Peigen Huang,Jian-Jian Li,Shalin S Patel,Cristina R Ferrone,Nan Zhang,Xiaoyan Liu,Hang Lee,Yuan Qi,Michael W Epperly,Albert B Deleo,Wende Li,Alphonse Taghian,Soldano Ferrone,Juan Cong,Xinhui Wang,Francesco Sabbatino,Amy Ly

doi:10.18632/oncotarget.1992

Yangyang Wang, Elena F Brachtel + Show 17 more

Open Access

https://doi.org/10.18632/oncotarget.1992

Copy DOI

Abstract

The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.

Highlights

Adjuvant radiation therapy (RT) is given to the breast cancer patients after conservation surgery and may be given to the chest wall after mastectomy to achieve better local tumor control improving survival of patients [1,2,3]
Based on compelling evidence showing that elevated aldehyde dehydrogenase (ALDH) activity in human and mouse breast cancer (BC) cells is a marker for breast cancer stem cells (BCSCs) and induced BCSCs (iBCSCs) [6, 12,13,14], in this study we have identified these cells by flow cytometry analysis of BC cells as ALDHbright cells, namely those ALDH+ cells with twice the mean fluorescence intensity (MFI) of the bulk ALDH+ cell population
The increased percentage of BCSCs was caused by an increase in the absolute number of BCSCs accompanied by a 50.5% decrease in total cell number in irradiated cells vs. untreated cells, which indicates that IR induced the formation of new BCSCs or iBCSCs (Fig. 1A)

Summary

Introduction

Adjuvant RT is given to the breast cancer patients after conservation surgery and may be given to the chest wall after mastectomy to achieve better local tumor control improving survival of patients [1,2,3]. Radioresistance impedes the anti-tumor effects of RT and could be attributed to BCSCs, since it has recently been www.impactjournals.com/oncotarget shown that BCSCs are radioresistant[4, 5]; but radiation can induce BCSCs, i.e., iBCSCs from nonstem breast cancer cells [6]. In order to significantly improve the efficacy and curability of RT for breast cancer, novel therapeutic approaches are urgently needed to eliminate radioresisitant pre-existing BCSCs, and block the formation of radiation induced new BCSCs from nonstem BC cells. IR has been shown to reprogram differentiated cancer cells into iBCSCs or liver CSCs through the re-expression or upexpression of the stemness genes Oct4/SOX2/Nanog/ KLF4 and SOX2/OCT3/Oct, respectively [6, 11]

Methods

Results

Conclusion