ANNEXIN A1 AS A FAILSAFE MECHANISM FOR BREAST CANCER BRAIN COLONIZATION

Abstract

Brain metastases in breast cancer is becoming increasingly common due to improved treatment modalities. Microglia are key components of the brain metastatic microenvironment. This study uncovered a network paracrine signaling between metastatic breast cancer cells and microglia involving AnnexinA1 (ANXA1), a glucocorticoid-regulated protein endowed with anti-inflammatory and pro-resolving properties. 4T1 metastatic mammary cancer cells overexpress and externalize ANXA1 to promote directed migration of BV-2 microglia and imparts its immunomodulatory effects on microglia by inducing gene expression of IL-6, IL-10, and CD206 via interaction with formyl-peptide receptors (FPRs). The secretome of 4T1 metastatic mammary cancer cells also triggers a parallel increase in the expression of ANXA1 in microglia to maintain activation of STAT3 induced by FPRs stimulation. This study also demonstrated the significant anti-tumour effects of ANXA1 deletion in vivo. The findings of this study capture a pro-tumourigenic and pro-metastatic program driven by ANXA1 via multi-level regulation of STAT3.