The lipid-transfer protein Nir2 enhances epithelial-mesenchymal transition and facilitates breast cancer metastasis

Abstract

The involvement of Epithelial-mesenchymal transition (EMT) in breast cancer metastasis has been demonstrated by many studies. However, the intracellular proteins and signaling pathways that regulate EMT have not been fully identified. Here we show that the lipid-transfer protein Nir2 enhances EMT in mammary epithelial and breast cancer cells. Nir2 overexpression induces down-regulation of epithelial markers and concomitant up-regulation of mesenchymal markers, while silencing of Nir2 by shRNA has opposite effects. Additionally, Nir2 expression is increased during EMT and affects cell morphology, while Nir2 depletion attenuates growth factor-induced cell migration. These effects of Nir2 on EMT-associated processes are mainly mediated through the PI3K/AKT and the ERK1/2 pathways. Nir2 depletion also inhibits cell invasion in vitro and lung metastasis in animal models. Immunohistochemical analysis of breast cancer tissue samples reveals a correlation between high Nir2 expression and tumor grade, and Kaplan–Meier survival curves correlate Nir2 expression with poor disease outcome. These results suggest that Nir2 not only enhances EMT in vitro and breast cancer metastasis in animal models, but also contributes to breast cancer progression in human patients.