NRF2 promotes breast cancer cell proliferation and metastasis by increasing RhoA/ROCK pathway signal transduction
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Chao Zhang1,2, Hui-Jie Wang1,2, Qi-Chao Bao1,2, Lei Wang1,2, Tian-Kun Guo1,2, Wei-Lin Chen1,2, Li-Li Xu1,2, Hai-Shan Zhou1,2, Jin-Lei Bian1,2, Ying-Rui Yang1,2, Hao-Peng Sun1,2,3, Xiao-Li Xu1,2,3, Qi-Dong You1,2,3
1Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China
2State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
3Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
Xiao-Li Xu, email: [email protected]
Qi-Dong You, email: [email protected]
Keywords: NRF2, breast cancer, RhoA/ROCK pathway, cell proliferation, metastasis
Received: January 04, 2016 Accepted: September 26, 2016 Published: October 04, 2016
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 silencing-mediated reduction of RhoA expression contributes, at least in part, to the poor outcome of breast cancer patients with high NRF2 expression.
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