SAT-335 Resistin Induces Epithelial to Mesenchymal Transition (EMT) in Breast Cancer Cells through Activation of AXL Tyrosine Kinase Receptor

Resistin is an adipokine produced by the white adipose tissue that associates with breast cancer progression. Our previous studies demonstrated that resistin increases cancer motility by inducing epithelial to mesenchymal transition (EMT) and acquisition of cancer stem cell properties in breast cancer cells. AXL is a tyrosine kinase receptor belonging to the tumor-associated macrophage family which regulates a variety of processes including cell survival, growth, aggregation, migration, etc. Previous reports indicate that AXL also plays a significant role in tumor growth and progression, suppressing cell apoptosis and inducing angiogenesis and cancer metastasis. The aim of this study was to investigate whether the resistin effects on EMT are mediated by AXL. Using quantitative PCR array followed by qRT-PCR analysis, we found that in MCF-7 and MDA-MB-231 breast cancer cells resistin significantly upregulated mRNA expression levels of AXL and mesenchymal cell markers (SNAIL, SLUG, and ZEB1 transcription factors and their target genes fibronectin and vimentin), concomitantly inducing SNAIL and ZEB1 nuclear translocation. In order to investigate whether AXL participates in the molecular mechanism by which resistin affects EMT, we used short-interfering RNA to silence AXL mRNA expression or a chemical approach (R428) to suppress AXL activity. Either, AXL siRNA or R428, significantly blocked the effects of resistin on the expression of mesenchymal markers as well as inhibited resistin-induced nuclear translocation of SNAIL and ZEB1. Taken together, these results demonstrate that activation of AXL mediates the effects of resistin on EMT. Additional experiments are in progress.