RAGE Mediates S100A7-Induced Breast Cancer Growth and Metastasis by Modulating the Tumor Microenvironment

Abstract

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-κB 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.

Increased Expression of the Receptor for Advanced Glycation End-Products (RAGE) Is Associated with Advanced Breast Cancer Stage

“…In this study, we demonstrated that RAGE is expressed in a set of aggressive breast cancer samples, TNBC and metastatic and node-positive cancerous tissues. This is consistent with a recent report that revealed that high RAGE expression was observed in node-positive and metastatic breast cancer [28]. A notable difference between our study and the previous study is the evaluation of RAGE expression based on more clinicopathological characteristics, e.g., tumor size, nodal status, hormone receptor status, HER2 status, lymphovascular invasion, and correlation studies.…”

Conditioning solid tumor microenvironment through inflammatory chemokines and S100 family proteins

“…As shown in our model (Fig. 2), S100A7 binds to RAGE and RAGE/ S100A7 axis modulates the breast TME through recruitment of MMP9-positive TAMs [78]. More recently, it has also been shown that cancer associated adipocyte tissues enhance breast cancer progression through enhancing the expression of S100A7 and S100A8/9 chemokines [79].…”

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

“…The current study adds to the previous knowledge by revealing a strong potentiating influence of S100A4, which is expressed at elevated levels in basal‐like/TNBC as also reported previously (Egeland et al ., 2017). Furthermore, TNBC shows elevated expression of TLR4 and RAGE receptors (Mehmeti et al ., 2015; Nasser et al ., 2015), which have been linked to S100A4‐trigged cytokine induction (Cerezo et al ., 2014; Haase‐Kohn et al ., 2011). …”