Connecting RAGE and cell plasticity in triple-negative breast cancer

Abstract

RAGE is a transmembrane protein of the immunoglobulin family highly expressed during embryonic development but rarely expressed in adult healthy tissues. However, under cellular stress RAGE is re-expressed and mediates inflammatory chronic diseases including diabetes, Alzheimer’s and cancer. RAGE is a multi-ligand receptor and its protein ligands, which are unconventionally secreted, are overexpressed under inflammatory conditions, activating RAGE-driven signaling pathways.

The aim of this thesis is to study the involvement of RAGE in Triple Negative Breast Cancer (TNBC) progression. First, we show that breast cancer (BC) cells exposed to different microenvironmental stresses become more migratory and invasive. Under acute acidosis, the secretome of different BC cells is enriched with RAGE ligands. Moreover, acidosis induces an oligomerization of RAGE, which correlates with its signaling activation. In BC cells, ligand binding to RAGE activates NF-kB and/or ERK1/2 pathways promoting breast cancer cell migration and invasion. Both the ablation of RAGE expression and its inhibition using RAGE antagonists block RAGE- mediated signaling and cell migration and invasion in TNBC cells. Furthermore, blocking RAGE in mesenchymal TNBC cells induces a mesenchymal-to-epithelial transition (MET) by down-regulating SNAIL1 expression. TNBC mesenchymal cells under RAGE inhibition gain the expression of several epithelial markers, increase cell adhesions and become less invasive. Furthermore, in a TNBC in vivo model, we show that treatment with a RAGE antagonist reduces the incidence of metastasis and increases overall survival. Therefore, this study shows that RAGE drives EMT and tumor cell invasion in mesenchymal TNBC cells, and it shows that RAGE is a new candidate therapeutic target for breast cancer.