Characterizing an EMT Signature in Breast Cancer
Annual summary rept. 1 Apr 2008-31 Mar 2009
LELAND STANFORD JUNIOR UNIV CA
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Epithelial-to-mesenchymal transition EMT, a switch of polarized epithelial cells to a migratory, fibroblastoid phenotype, is increasingly considered a determining step for cancer cell invasiveness and metastasis. To identify new molecular markers and potential key regulators of EMT, we performed expression profiling comparing 10 epithelial-like and 5 fibroblast-like breast cancer cell lines, subtracting the gene signatures from 5 early-passage normal breast fibroblast cell cultures. Differentially expressed genes were used to generate a 200- gene EMT signature, which was evaluated for its association with overall survival in patients with breast cancer. In published microarray cohorts there was significant association between the EMT signature and clinical outcome in patients with breast cancer, which was independent of established clinical and pathological variables p0.05. Among highly-ranked EMT signature genes, we also investigated the role of LYN, a member of the Src-family kinases. LYN expression, assayed by immunohistochemistry on tissue microarrays, was observed in 14.2 of breast cancer cases, and was associated with shorter overall survival p0.02, and correlated with the basallike triple-negative phenotype. Knockdown of LYN by RNA interference in fibroblast-like breast cancer cell lines inhibited cell migration and invasion, but not cell proliferation. Our findings define a prognostically-relevant EMT signature in breast cancer, and implicate LYN as a mediator of invasion and possible new therapeutic target, with particular relevance to clinically-aggressive basal-liketriple-negative breast cancer.
- Medicine and Medical Research