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LYN Is a Mediator of Epithelial-Mesenchymal Transition and a Target of Dasatinib in Breast Cancer

Cited 103 time in Web of Science Cited 101 time in Scopus
Authors
Choi, Yoon-La; Melanie Bocanegra; Kwon, Mi Jeong; Shin, Young Kee; Nam, Seok Jin; Yang, Jung-Hyun; Jessica Kao; Andrew K. Godwin; Jonathan R. Pollack
Issue Date
2010-03
Publisher
Cancer Research
Citation
Cancer Res; Vol.70(6); pp.2296–2306
Abstract
Epithelial-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.
ISSN
0008-5472
Language
English
URI
https://hdl.handle.net/10371/73455
DOI
https://doi.org/10.1158/0008-5472.CAN-09-3141
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Journal Papers (저널논문_약학과)
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