RAGE mediates S100A7-induced breast cancer growth and metastasis by modulating the tumor microenvironment

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en favorisant le recrutement de macrophages associés aux tumeurs dans le micro-environnement tumoral, la surexpression du récepteur multi-fonctionnel RAGE favorise la croissance tumorale et le processus métastatique d'un cancer du sein triplement négatif

Résumé en anglais

RAGE is a multi-functional receptor implicated in diverse processes including inflammation and cancer. In this study, we report that RAGE expression is upregulated widely in aggressive triple-negative breast cancer cells, both in primary tumors and lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found RAGE-deficient mice displayed a reduced propensity for breast tumor growth. In an established model of lung metastasis, systemic blockade by injection of a RAGE neutralizing antibody inhibited metastasis development. Mechanistic investigations revealed that RAGE bound to the pro-inflammatory ligand S100A7 and mediated its ability to activate ERK, NF-ĸB and cell migration. In an S100A7 transgenic mouse model of breast cancer (mS100a7a15 mice), administration of either RAGE neutralizing antibody or soluble RAGE was sufficient to inhibit tumor progression and metastasis. In this model, we found that RAGE/S100A7 conditioned the tumor microenvironment by driving the recruitment of MMP9-positive tumor-associated macrophages. Overall, our results highlight RAGE as a candidate biomarker for triple-negative breast cancers and they reveal a functional role for RAGE/S100A7 signaling in linking inflammation to aggressive breast cancer development.