Loss of Wwox drives metastasis in triple-negative breast cancer by JAK2/STAT3 axis

Renxu Chang,Cheng Dai,Xianbao Zhan,Xinyu Wang,Wei Li,Yingyong Hou,Yi Xu,Lele Song,Yanjun Wu,Xia Sun,Lixing Zhan

doi:10.1038/s41467-018-05852-8

Abstract

Loss of WW domain-containing oxidoreductase (Wwox) expression has been observed in breast cancer (BC). However, its regulatory effects are largely unknown, especially in triple-negative breast cancer (TNBC). Herein, gene expression profiling revealed that JAK/STAT3 pathway was one of the most differentially modulated pathways in basal-like BC cells. The lower expression of Wwox was significantly correlated with high activation of STAT3 in basal-like cells and TNBC tissues. Overexpression of Wwox markedly inhibited proliferation and metastasis of BC cells by suppressing STAT3 activation, which is to interact with JAK2 to inhibit JAK2 and STAT3 phosphorylation. Furthermore, Wwox limited STAT3 binding to the interleukin-6 promoter, repressing expression of the IL-6 cytokine. Altogether, our data established that Wwox suppresses BC cell metastasis and proliferation by JAK2/STAT3 pathway. Targeting of Wwox with STAT3 could offer a promising therapeutic strategy for TNBC.

Highlights

Loss of WW domain-containing oxidoreductase (Wwox) expression has been observed in breast cancer (BC)
We characterized the level of Wwox protein in BC cells, and Wwox protein was expressed at much lower levels in basal-like cells than in luminal cells (Fig. 1a)
Wwox was highly expressed in luminal BC cells that exhibited very low levels of phosphorylated STAT3 (p-STAT3; Fig. 1a)

Summary

Introduction

Loss of WW domain-containing oxidoreductase (Wwox) expression has been observed in breast cancer (BC). The lower expression of Wwox was significantly correlated with high activation of STAT3 in basal-like cells and TNBC tissues. Overexpression of Wwox markedly inhibited proliferation and metastasis of BC cells by suppressing STAT3 activation, which is to interact with JAK2 to inhibit JAK2 and STAT3 phosphorylation. Loss of Wwox expression has been observed in cancers of many organs, including breast, lung, esophageal, and gastric carcinomas[11,14,15,16,17,18]. We found that Wwox affects the IL-6/JAK2/ STAT3 (interleukin-6/Janus kinase-2/signal transducer and activator of transcription-3) axis, inhibiting cancer cell growth and metastasis in a STAT3-dependent manner

Methods

Results

Conclusion