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

• Published in: Nature communications 2018-08, Vol.9 (1), p.3486-12, Article 3486
• Main Authors: Chang, Renxu, Song, Lele, Xu, Yi, Wu, Yanjun, Dai, Cheng, Wang, Xinyu, Sun, Xia, Hou, Yingyong, Li, Wei, Zhan, Xianbao, Zhan, Lixing
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/51; 13/89; 38/15; 38/39; 38/89; 42/70; 42/89; 631/67/1244; 631/67/1347; Activation; Animals; Blotting, Western; Breast cancer; Cancer; Cell Line, Tumor; Cell Movement - genetics; Cell Movement - physiology; Cell proliferation; Cell Proliferation - genetics; Cell Proliferation - physiology; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Female; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Gene Expression Regulation, Neoplastic - physiology; Humanities and Social Sciences; Humans; Immunoprecipitation; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Janus kinase 2; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; multidisciplinary; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; NIH 3T3 Cells; Oxidoreductase; Phosphorylation; Science; Science (multidisciplinary); Signal Transduction; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; WW Domain-Containing Oxidoreductase - genetics; WW Domain-Containing Oxidoreductase - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05852-8

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. In breast cancer, the loss of expression of WW domain-containing oxireductase (Wwox) has been observed. Here, the authors illustrate that in triple negative breast cancer models Wwox suppresses metastasis and proliferation via the JAK2/STAT3 pathway.