Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation

Peiguo Shi,Rong Liu,Wenlin Chen,Ceshi Chen,Zhongmei Zhou,Chunyan Wang,Yanjie Kong,Tala Tala,Fubing Li,Wenjing Liu,Yingying Wu,Haixia Wang,Hailin Zhang

doi:10.1038/celldisc.2017.10

Abstract

Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanism of action of metformin in TNBC are unclear. In this study, we demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of the stem cell transcription factor Krüppel-like factor 5 (KLF5) and its downstream target genes, such as Nanog and FGF-BP1, in TNBC cell lines. Metformin induced glycogen synthase kinase-3β (GSK3β)-mediated KLF5 protein phosphorylation and degradation through the inhibition of protein kinase A (PKA) activity in TNBC cells. Consistently, PKA activators increased the expression levels of KLF5. We observed a positive correlation between p-CREB, p-GSK3β, KLF5 and FGF-BP1 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3β-KLF5 signaling pathway.

Highlights

Breast cancer is the most common cancer in women in China and the United States
Metformin suppresses Triple-negative breast cancer (TNBC) stem cells To test whether metformin decreases the percentage of TNBC stem cells in TNBC-derived cell lines, we assessed the expression of the breast cancer stem cell biomarker aldehyde dehydrogenase (ALDH) [27]
Accumulating data suggest that metformin combined with other chemotherapeutics or radiotherapy may be used for the treatment of breast cancer

Summary

Introduction

Breast cancer is the most common cancer in women in China and the United States. China was estimated to have 268 600 new cases in 2015, and the United States was estimated to have 246 660 new cases in 2016 [1, 2]. Triple-negative breast cancer (TNBC; estrogen receptor α-, progesterone receptor and HER2-negative) is the subtype of breast cancer with the poorest prognosis due to a lack of targeted therapies [3]. TNBC can further be divided into different subtypes, including the basal-like and claudin-low subtypes [4]. Basal-like TNBC accounts for ~ 80% of TNBC [4].

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Results

Conclusion