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

Mohd W. Nasser, Nissar Ahmad Wani, Dinesh K. Ahirwar, Catherine A. Powell, Janani Ravi, Mohamad Elbaz, Helong Zhao, Laura Padilla, Xiaoli Zhang, Konstantin Shilo, Michael Ostrowski, Charles Shapiro, William E. Carson, Ramesh K. Ganju

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58 Scopus citations

Abstract

RAGE is a multifunctional 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 (TNBC) cells, both in primary tumors and in lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found that 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 proinflammatory 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 TNBCs, and they reveal a functional role for RAGE/S100A7 signaling in linking inflammation to aggressive breast cancer development.

Original languageEnglish (US)
Pages (from-to)974-985
Number of pages12
JournalCancer Research
Volume75
Issue number6
DOIs
StatePublished - Mar 15 2015

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nasser, M. W., Wani, N. A., Ahirwar, D. K., Powell, C. A., Ravi, J., Elbaz, M., Zhao, H., Padilla, L., Zhang, X., Shilo, K., Ostrowski, M., Shapiro, C., Carson, W. E., & Ganju, R. K. (2015). RAGE mediates S100A7-induced breast cancer growth and metastasis by modulating the tumor microenvironment. Cancer Research, 75(6), 974-985. https://doi.org/10.1158/0008-5472.CAN-14-2161