LYN is a mediator of epithelial-mesenchymal transition and a target of dasatinib in breast cancer.
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.
Choi
Yoon-La
YL
Department of Pathology and Division of Breast and Endocrine Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Bocanegra
Melanie
M
Kwon
Mi Jeong
MJ
Shin
Young Kee
YK
Nam
Seok Jin
SJ
Yang
Jung-Hyun
JH
Kao
Jessica
J
Godwin
Andrew K
AK
Pollack
Jonathan R
JR
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000069439:Dasatinib