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

// Chao Zhang 1, 2 , Hui-Jie Wang 1, 2 , Qi-Chao Bao 1, 2 , Lei Wang 1, 2 , Tian-Kun Guo 1, 2 , Wei-Lin Chen 1, 2 , Li-Li Xu 1, 2 , Hai-Shan Zhou 1, 2 , Jin-Lei Bian 1, 2 , Ying-Rui Yang 1, 2 , Hao-Peng Sun 1, 2, 3 , Xiao-Li Xu 1, 2, 3 , Qi-Dong You 1, 2, 3 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China 3 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China Correspondence to: Xiao-Li Xu, email: xuxiao_li@126.com Qi-Dong You, email: youqidong@gmail.com Keywords: NRF2, breast cancer, RhoA/ROCK pathway, cell proliferation, metastasis Received: January 04, 2016      Accepted: September 26, 2016      Published: October 04, 2016 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 silencing-mediated reduction of RhoA expression contributes, at least in part, to the poor outcome of breast cancer patients with high NRF2 expression.