Abstract Epithelial-mesenchymal transition (EMT) is a cellular mechanism long recognized as a central feature of normal development, such as neural crest formation and heart morphogenesis. More recent studies have reported that physiopathological transitions occur during the progression of epithelial tumors, endowing cancer cells with increased motility and invasiveness. EMT implicated that epithelial cells become elongated, lose their polarity and cellular junctions, and show mesenchymal fibroblast-like properties. The role of estrogen and estrogen receptor (ER) in breast cancer cell motility and invasion is controversial. Although ER-positive breast tumors are considered less aggressive and more differentiated, they still undergo metastasis. Human antigen R (HuR) represents one of the best characterised RNA-binding proteins. HuR is involved in mRNA shuttling between nuclear and cytoplasmic compartments and has been shown to increase stability of many mRNA. In recent reports, HuR might serve as a central step in the control of the expression of factors that are involved in tumor growth and angiogenesis, and also plays a critical role in the control of ER mRNA stability. In this study, we investigated whether ginsenoside Rg3 could inhibit the 17β-estradiol (E2)-induced EMT via HuR in MCF-7 human breast cancer cell. Upon E2 stimulation, the levels of epithelial markers, E-cadherin and γ-catenin were strikingly suppressed, whereas those of mesenchymal markers, vimentin, α-SMA, β-catenin and HuR were significantly up-regulated. E2 stimulated the transfer of HuR protein from nucleus into cytoplasm. HuR down-regulated (HuR-DR) MCF-7 cells were established using the HuR shRNA plasmid. Down regulation of HuR did not change the levels of E-cadherin and ER-α, but decreased the levels of β-catenin and vimentin in E2-stimulated MCF-7 cells. Cell proliferation, migration and invasion was not affected by E2 in HuR-DR MCF-7 cells. Rg3 decreased the viability, migration and invasion of MCF-7 cells in the absence or presence of E2. Rg3 treatment inhibited EMT, evidenced by the increased expression of E-cadherin and ER-α, and the decreased expression of β-catenin and vimentin as compared with E2 stimulation. Rg3 inhibited E2-induced expression and cytoplasmic translocalization of HuR protein. In a mouse xenograft model, Rg3 attenuated tumor growth of MCF-7 cells and blocked expressions of EMT marker proteins and HuR, whereas HuR-DR MCF-7 cells did not result in tumor growth. Therefore, Rg3 inhibited E2-stimulated migration, invasion and growth by blocking E2-induced EMT via HuR as well as tumor growth in MCF-7 cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3374. doi:10.1158/1538-7445.AM2011-3374