Abstract P4-04-13: S100a7/rage signaling promotes breast tumorigenesis through modulating tumor-associated macrophages

Abstract

Abstract S100A7 has been shown to be associated with breast cancer growth and metastasis. However, the molecular mechanism through which S100A7 promotes breast tumorigenesis is not completely understood. In this study, we revealed that S100A7 enhanced Stat3-mediated secretion of Serpin-E1 in triple negative breast cancer (TNBC) cell lines. Serpin-E1 has been shown to promote recruitment and polarization toward a pro-tumorigenic phenotype of tumor-associated macrophages through activating the Stat3 pathway. Importantly, we reported that the inhibition of Stat3 led to reduction of S100A7-mediated invasiness of TNBC cells and also significantly decreased the secretion of Serpin-E1 by cancer cells. We also revealed that Stat3 inhibition in TNBC cells or Serpin-E1 neutralization significantly reduced the migration of human monocytes/macrophages by transwell migration assay. We further demonstrate that murine ortholog of S100A7, mS100a7a15 enhanced mammary hyperplasia, tumor growth and metastasis through Stat3 activation. Previously, we reported that S100A7 mediated its tumorigenic effects through RAGE in breast cancer cells. Therefore, we also discovered that combinatorial treatment of Stat3 and RAGE inhibitors in mammary tumor bearing mS100a7a15 overexpression mouse model strongly decreased the tumor burden and enhanced the recruitment of tumor-suppressing M1-macrophages. We also found that combined inhibition of RAGE and Stat3 significantly increased the infiltration of CD4 T cells in the tumor microenvironment (TME). Collectively, these findings suggest S100A7/RAGE signaling pathway could be used as a novel therapeutic target to inhibit breast cancer growth and metastasis through modulating the TME. Citation Format: Ajeet K Verma, Tasha Wilkie, Sanjay Mishra, Manish Charan, Ramesh K Ganju. S100a7/rage signaling promotes breast tumorigenesis through modulating tumor-associated macrophages [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-13.