17β-estradiol enhances breast cancer cell motility and invasion via extra-nuclear activation of actin-binding protein ezrin17β-estradiol提高乳腺癌细胞的能动性和入侵通过extra-nuclear actin-binding ezrin蛋白的激活.pdf

17b-Estradiol Enhances Breast Cancer Cell Motility and Invasion via Extra-Nuclear Activation of Actin-Binding Protein Ezrin 1. 1. 1 2 1 1 Shuhui Zheng , Jinghe Huang , Kewen Zhou , Chengxi Zhang , Qiuling Xiang , Zhi Tan , Tinghuai 1 1 Wang *, Xiaodong Fu * 1 Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China, 2 Department of Cardiovascular Internal Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Abstract Estrogen promotes breast cancer metastasis. However, the detailed mechanism remains largely unknown. The actin binding protein ezrin is a key component in tumor metastasis and its over-expression is positively correlated to the poor outcome of breast cancer. In this study, we investigate the effects of 17b-estradiol (E2) on the activation of ezrin and its role in estrogen- dependent breast cancer cell movement. In T47-D breast cancer cells, E2 rapidly enhances ezrin phosphorylation at Thr567 in a time- and concentration-dependent manner. The signalling cascade implicated in this action involves estrogen receptor (ER) interaction with the non-receptor tyrosine kinase c-Src, which activates the phosphatidylinositol-3 kinase/Akt pathway and the small GTPase RhoA/Rho-associated kinase (ROCK-2) complex. E2 enhances the horizontal cell migration and invasion of T47-D breast cancer cells in three-dimensional matrices, which is reversed by transfection of cells with specific ezrin siRNAs. In conclusion, E2 promotes breast cancer cell movement and invasion by the activation of ezrin. These results provide novel insights into the effects of estrogen on breast cancer progression and highlight potential targets