Abstract 147: Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation

Abstract

Abstract Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. A stem cell transcription factor KLF5 is over-expressed in basal type TNBC and promoting cell proliferation, survival and stemness. Previously, we demonstrated that Mifepristone suppresses basal TNBC stem cells by down-regulating KLF5 expression through inducing the expression of miR-153. In this study, 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. We demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of KLF5 and its downstream target genes, such as Nanog and FGF-BP1, in TNBC cell lines. Metformin induced GSK3β-mediated KLF5 protein phosphorylation and degradation through the inhibition of PKA activity in TNBC cells. Consistently, PKA activators increased the expression levels of KLF5. We observed a positive correlation between p-CREB and KLF5 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3β-KLF5 signaling pathway. Citation Format: Peiguo Shi, Zhongmei Zhou, Rong Liu, Ceshi Chen. Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 147. doi:10.1158/1538-7445.AM2017-147