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Choi YL , Bocanegra M , Kwon MJ , Shin YK , Nam SJ , Yang JH , Kao J , Godwin AK , Pollack JR
LYN Is a Mediator of Epithelial-Mesenchymal Transition and a Target of Dasatinib in Breast Cancer
Cancer Research. 2010 Mar;70(6) :2296-2306
AbstractEpithelial-mesenchymal transition (EMT), a switch of polarized epithelial cells to a migratory, fibroblastoid phenotype, is considered a key process driving tumor cell invasiveness and metastasis. Using breast cancer cell lines as a model system, we sought to discover gene expression signatures of EMT with clinical and mechanistic relevance. A supervised comparison of epithelial and mesenchymal breast cancer lines defined a 200-gene EMT signature that was prognostic across multiple breast cancer cohorts. The immunostaining of LYN, a top-ranked EMT signature gene and Src-family tyrosine kinase, was associated with significantly shorter overall survival (P = 0.02) and correlated with the basal-like ("triple-negative") phenotype. In mesenchymal breast cancer lines, RNAi-mediated knockdown of LYN inhibited cell migration and invasion, but not proliferation. Dasatinib, a dual-specificity tyrosine kinase inhibitor, also blocked invasion (but not proliferation) at nanomolar concentrations that inhibit LYN kinase activity, suggesting that LYN is a likely target and that invasion is a relevant end point for dasatinib therapy. Our findings define a prognostically relevant EMT signature in breast cancer and identify LYN as a mediator of invasion and a possible new therapeutic target (and theranostic marker for dasatinib response), with particular relevance to clinically aggressive basal-like breast cancer. Cancer Res; 70(6); 2296-306. (C) 2010 AACR.
NotesChoi, Yoon-La Bocanegra, Melanie Kwon, Mi Jeong Shin, Young Kee Nam, Seok Jin Yang, Jung-Hyun Kao, Jessica Godwin, Andrew K. Pollack, Jonathan R. NIH [CA97139, CA113916, CA09302, CA130172, N01-CN-43309]; Department of Defense [BC073467]; California Breast Cancer Research Program [8KB-0135]; Ministry of Education, Science and Technology [2009-0071010] Grant Support NIH grants CA97139 (J.R. Pollack), CA113916 (A. K. Godwin), CA09302 (M. Bocanegra), and CA130172 (M. Bocanegra); NIH contract N01-CN-43309 (A. K. Godwin); Department of Defense (BC073467); California Breast Cancer Research Program, 8KB-0135 (J.R. Pollack); and Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2009-0071010; Y-L. Choi). 49 Amer assoc cancer research; 615 chestnut st, 17th floor, philadelphia, pa 19106-4404 usa 607ga