Abstract 3363: RAGE/S100A7/Stat3-axis enhances breast cancer growth and metastasis via modulating tumor microenvironment

Abstract

Abstract The Receptor for Advanced Glycation Endproducts (RAGE), a multifunctional, multi-ligand receptor, has been shown to play an important role in inflammation. However, not much is known about its role in breast cancer growth and metastasis. In this report, we observed that RAGE expression is upregulated in triple negative breast cancer (TNBC) cell lines, primary tumors and lymph-node metastasis samples. RAGE-/- mice show reduced breast cancer growth. Additionally, blocking RAGE with neutralizing-antibody inhibited lung metastasis in an intracardiac mouse model. Further elucidation of RAGE-mediated mechanisms revealed that RAGE binds to S100A7 and mediates S100A7-induced cell migration, Stat3 and NF-ĸB activation. Our results also indicate that S100A7/RAGE axis-modulates invasion/migration through Stat3 dependent MMP9 activation. In addition, RAGE neutralizing antibody and soluble RAGE inhibited breast cancer progression and metastasis in the inducible mS100a7a15 mouse model system. We demonstrated that RAGE/S100A7 enhanced mammary hyperplasia, tumor growth and metastasis through Stat3 activation. Notably, our studies revealed that RAGE/mS100a7a15 modulates the breast tumor microenvironment through recruitment of phospho-Stat3/MMP9-positive tumor-associated macrophages. Our studies suggest that RAGE expression could be used as a novel biomarker for aggressive/invasive breast cancer, especially TNBC. Collectively, these findings suggest that RAGE/S100A7/Stat3-axis has a novel role in linking inflammation to the development of invasive/aggressive breast cancer including TNBC. Citation Format: Mohd W. Nasser, Nissar A. Wani, Janani Ravi, Grace A. Amponsah, Dinesh K. Ahirwar, Catherine A. Powell, Mohamad Elbaz, Helong Zhao, Konstantin Shilo, Ramesh K. Ganju. RAGE/S100A7/Stat3-axis enhances breast cancer growth and metastasis via modulating tumor microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3363. doi:10.1158/1538-7445.AM2015-3363