Ras Promotes Transforming Growth Factor-beta (TGF-beta)-induced Epithelial-Mesenchymal Transition via a Leukotriene B-4 Receptor-2-linked Cascade in Mammary Epithelial Cells

Abstract

Inflammation and inflammatory mediators are inextricably linked with epithelial-mesenchymal transition (EMT) through complex pathways in the tumor microenvironment. However, the mechanism by which inflammatory mediators, such as the lipid inflammatory mediators, eicosanoids, contribute to EMT is largely unknown. In the present study we observed that BLT2, leukotriene B-4 receptor-2, is markedly up-regulated by oncogenic Ras and promotes EMT in response to transforming growth factor-beta (TGF-beta) in mammary epithelial cells. Blockade of BLT2 by the BLT2 inhibitor LY255283 or by siRNA reduced EMT induced by Ras in the presence of TGF-beta. In addition, stimulation of BLT2 by the addition of a BLT2 ligand, such as leukotriene B-4, restored EMT in the presence of TGF-beta in human immortalized mammary epithelial MCF-10A cells. We further searched BLT2 downstream components and identified reactive oxygen species and nuclear factor kappa B as critical components that contribute to EMT. Taken together, these results demonstrate for the first time that a BLT2-linked inflammatory pathway contributes to EMT. This provides valuable insight into the mechanism of EMT in mammary epithelial cells. In addition, considering the implications of EMT with the stemness of cancer cells, our finding may contribute to a better understanding of tumor progression.