Breast Cancer Exosome-Derived miR-425-5p Induces Cancer-Associated Fibroblast-Like Properties in Human Mammary Fibroblasts by TGFβ1/ROS Signaling Pathway

The connection between the cellular microenvironment and tumor cells is crucial for tumor progression. However, the process by which normal fibroblasts (NFs) become cancer-associated fibroblasts (CAFs) is unknown, and mounting evidence suggests that some microRNAs (miRNAs) have an important role in converting NFs into CAFs. Breast cancer (BC) has been proven to have enhanced miR-425-5p expression in order to support progression. We discovered that human mammary fibroblasts (HMFs) could uptake BC cell line-derived exosomes to change their properties, promoting the switch to the CAF phenotype and increasing cell motility, as evidenced by an increase in CAF activation-related marker protein expression and cell proliferation, invasion, and migration. Transfection of exosomes is obtained from BC cells, and miR-425-5p inhibitors suppressed the aforementioned effects as well as lowered chemokine levels and gene expression related with proliferation and metastasis. By suppressing the expression of its target gene TGF beta RII (TGF beta 1 receptor), miR-425-5p enhanced the transition of HMFs to the CAF phenotype. MDA-MB-231 cells and CAFs stimulated by HMF absorption of MDA-MB-23-derived exosomes showed similar proliferation, invasion, migration, and expression of -SMA, FAP, CXCL1, IL-6, TGF beta 1, P21, P27, Ki67, vimentin, E-cadherin, N-cadherin, alpha-catenin, fibronectin, and MMP-2. TGF beta 1 overexpression enhanced ROS production. Finally, we found that HMFs transiently transfected with miR-425-5p can promote tumor growth in vivo. Finally, these findings provide fresh insight on miR-425-5p as an important mediator of the interaction between BC cells and stroma.

Automated summary

The microRNA miR-425-5p plays an important role in the interaction between breast cancer cells and fibroblasts. It promotes the conversion of fibroblasts into cancer-associated fibroblasts (CAFs), thereby supporting tumor progression and metastasis.