NRF2 promotes breast cancer cell proliferation and metastasis by increasing RhoA/ROCK pathway signal transduction

Chao Zhang, Hui Jie Wang, Qi Chao Bao, Lei Wang, Tian Kun Guo, Wei Lin Chen, Li Li Xu, Hai Shan Zhou, Jin Lei Bian, Ying Rui Yang, Hao Peng Sun, Xiao Li Xu, Qi Dong You

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

Nuclear factor erythroid 2-related factor (NRF2) is an important transcription factor in oxidative stress regulation. Overexpression of NRF2 is associated with human breast carcinogenesis, and increased NRF2 mRNA levels predict poor patient outcome for breast cancer. However, the mechanisms linking gain of NRF2 expression and poor prognosis in breast cancer are still unclear. Here, we provide evidence that NRF2 deletion inhibits proliferation and metastasis of breast cancer cells by down-regulating RhoA. Restoration of RhoA in MCF7 and MDA-MB-231 cells induced NRF2 knockdown-suppressed cell growth and metastasis in vitro, and NRF2 silencing suppressed stress fiber and focal adhesion formation leading to decreased cell migration and invasion. Mechanistic studies showed that NRF2 binds to the promoter region of estrogen-related receptor α (ERR1) and may function as a silencer. This may enhance RhoA protein stability and lead to RhoA overexpression in breast cancer cell. Our findings indicate that NRF2 silencingmediated reduction of RhoA expression contributes, at least in part, to the poor outcome of breast cancer patients with high NRF2 expression.

Original languageEnglish (US)
Pages (from-to)73593-73606
Number of pages14
JournalOncotarget
Volume7
Issue number45
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • Breast cancer
  • Cell proliferation
  • Metastasis
  • NRF2
  • RhoA/ROCK pathway

ASJC Scopus subject areas

  • Oncology

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