It has been well documented that activation of the ErbB3-PI3K-Akt pathway is implicated in tumor survival and progression. We previously demonstrated that the single N-glycan deletion mutant of soluble ErbB3 protein (sErbB3 N418Q) attenuates heregulin beta 1-induced ErbB3 signaling. The active PI3K-Akt pathway augments the nuclear accumulation of hypoxia inducible factor (HIF)-1 alpha, which activates the transcription of many target genes and drives cancer progression. In this study, we focused on the effects of sErbB3 N418Q mutant on nuclear accumulation of HIF-1 alpha. Pretreatment with the sErbB3 N418Q mutant suppressed heregulin beta 1-induced HIF-1 alpha activation in MCF7 cells. Similar results were also obtained in other breast cancer cell lines, T47D and BT474. Interestingly, these suppressive effects were not observed with the sErbB3 wild type. In addition, pretreatment with the sErbB3 N418Q mutant suppressed the cell migration of MCF7 cells induced by heregulin beta 1. Furthermore, incubation with heregulin beta 1 also induced the nuclear accumulation of Nrf2, and this effect was also reduced by the sErbB3 N418Q mutant, but not the sErbB3 wild type. These findings indicated that the sErbB3 N418Q mutant suppressed malignant formation of cancer cells by blocking of the H1F-1 alpha and Nrf2 pathways. (C) 2014 Elsevier Inc. All rights reserved.