ESM1 IS INVOLVED IN CROSSTALK BETWEEN ACTIVATED FIBROBLASTS AND BREAST CANCER CELLS TO PROMOTE TUMOR PROGRESSION

The proteoglycan ESM1 (Endothelial cell-specific molecule 1) is involved in the pathogenesis of various diseases, including breast cancer (BC), where it is aberrantly expressed and contributes to cell proliferation, migration, and angiogenesis1. Stromal fibroblasts can be activated by tumor cells to differentiate into cancer-associated fibroblasts (CAFs), which promote tumor progression, metastasis, and invasion by secreting growth-promoting and proangiogenic factors 2. Based on this evidence, we investigated the role of ESM1 in a co-culture model of mammary fibroblasts and BC cells to clarify its involvement in tumor progression. Mammary fibroblasts were seeded in the lower chamber of a transwell system, while either MCF-7 (non-aggressive) or MDA-MB231 (aggressive) breast cancer cells were placed in the upper chamber. Further groups of cells were treated with either ESM1-specific siRNA or control siRNA.After 24 h of co-culturing, a significant increase of ESM1 mRNA and protein levels was found in both BC cells and activated mammary fibroblasts. Furthermore, BC cells exhibited increased expression of MMP-9, vimentin, and other markers associated with proliferation, migration, and epithelial-mesenchymal transition. Notably, ESM1 knockdown in fibroblasts, as well as in BC cells, reduced all these parameters. These results suggest that ESM1 produced by both activated fibroblasts and BC cells plays a key role in enhancing breast cancer cell aggressiveness by modulating markers associated with tumor progression. This revealed the impact of ESM1 in the crosstalk between activated fibroblasts and breast cancer cells indicating a new mechanism through which the tumor microenvironment may drive tumor progression.