Oncotarget

Research Papers:

Yap1 promotes the survival and self-renewal of breast tumor initiating cells via inhibiting Smad3 signaling

Jian-Guo Sun _, Xie-Wan Chen, Lu-Ping Zhang, Jiang Wang, Max Diehn

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Abstract

Jian-Guo Sun1,2, Xie-Wan Chen2, Lu-Ping Zhang2, Jiang Wang2 and Max Diehn1

1 Cancer Institute, Stanford University School of Medicine, Stanford, California, USA

2 Department of Oncology, Second Affiliated Hospital of Third Military Medical University, Chongqing, P.R. China

Correspondence to:

Jian-Guo Sun, email:

Max Diehn, email:

Keywords: Yap1, breast cancer, tumor initialing cells, self-renewal, Smad3

Received: June 06, 2015 Accepted: October 08, 2015 Published: December 18, 2015

Abstract

Tumor initiating cells (TICs) serve as the root of tumor growth. After identifying TICs in spontaneous breast tumors of the MMTV-Wnt1 mouse model, we confirmed the specific expression and activation of Yes-associated protein 1 (Yap1) within TICs. To investigate the role of Yap1 in the self-renewal of breast TICs and the underlying mechanism, we sorted CD49fhighEpCAMlow cells as breast TICs. Active Yap1 with ectopic expression in breast TICs promoted their colony formation in vitro (p< 0.01) and self-renewal in vivo (p< 0.01), and led to a 4-fold increase in TIC frequency (p< 0.05).A conditional knock-out mouse was reconstructed to generate Yap1 knock-out breast tumors. The loss of Yap1 led to a dramatic growth disadvantage of breast TICs in vitro (p< 0.01) and in vivo (p< 0.01), and it also led to an over 200-fold decrease in TIC frequency (p< 0.01). The expression of active Yap1 was negatively correlated with that of phosphorylated Smad3 (p-Smad3).Transforming growth factor β (TGF-β) served as a strong enhancer of Smad3 and an inhibitor of clonogenesis of TICs. The presence of SIS3, a specific inhibitor of Smad3, could rescue the TGF-β -induced growth inhibition and reverse the Smad3 inhibition by Yap1. Analysis of a database containing 2,072 human breast cancer samples showed that higher expressions of Yap1 correlated with a poorer outcome of a 15-year survival rate and median overall survival (mOS)in patients, especially in those with basal breast tumors without estrogen receptor 1 (ER) expression. The findings indicate that active Yap1 promotes the self-renewal of breast TICs by inhibiting Smad3 signaling.

Author Information

Jian-Guo Sun
Primary Contact  _

Xie-Wan Chen

Lu-Ping Zhang

Jiang Wang

Max Diehn


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