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

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. Cancer Res; 70(6); 2296-306. ©2010 AACR.

Polygenic in vivo validation of cancer mutations using transposons

“…Expression of both the wild-type and S768F mutant allele of endoplasmic reticulum to nucleus signalling 1 (ERN1, also IRE1) are the second and fourth most frequently recovered transposon cDNAs in our study (Table 2), corroborating recent description of ERN1 as playing key roles in tumour angiogenesis, growth and invasion [26,27]. In contrast, for the v-yes-1 Yamaguchi sarcoma viral related oncogene homologue (LYN) kinase that is implicated in a wide variety of cancers [28][29][30], while expression of the wild-type kinase is the third most frequent occurrence, we never recovered any tumours expressing the D385Y mutant ( Table 2). This would suggest that the D385Y mutation is potentially a loss-of-function mutation, though this has to be characterised molecularly with biochemical and cellbased activity assays.…”

Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells

“…Dasatinib reduced migration and invasion in head and neck squamous cell carcinoma, non-small cell lung cancer [29] and in breast cancer cell lines [30,31]. Interestingly, basal-like/triplenegative breast cancer cell lines with high levels of caveolin-1 expression, like MDA-MB-231 cells, are characterized by sensitivity to Dasatinib, while low expression of caveolin-1 correlates with resistance [32].…”

Combined inhibition of AXL, Lyn and p130Cas kinases block migration of triple negative breast cancer cells

“…Lyn has been described as an important target in haematopoietic and solid tumors including TNBC, and was proven to be one of the most overexpressed kinase in TNBC cell lines. 29,33 Lyn plays an important role in the migration of cancer cells and was shown that can interact with p130Cas, one of the member of the focal adhesion complex. 34 Association of p130Cas with motility, invasion and survival of TNBC cells has been shown before by several publications.…”

“…33 Based on these result we selected Lyn to analyze its function on the migration and viability of MDA-MB-231, Hs578T and BT549 cells. It is known that Lyn interacts 34 with one of the members of the focal adhesion complex, namely p130Cas.…”