# Recombinant Human Decorin Normalizes the Active Features of Breast Cancer-Associated Fibroblasts

## TL;DR

Recombinant human decorin can reduce the harmful effects of cancer-associated fibroblasts in breast cancer without causing cell death.

## Contribution

rhDCN persistently normalizes active breast cancer-associated fibroblasts without cytotoxicity.

## Key findings

- rhDCN repressed active CAF biomarkers like α-SMA, IL-6, and SDF-1 via the STAT3/AUF-1 pathway.
- rhDCN suppressed FAP-α, reduced proliferation and invasion, and inhibited EMT and cancer stem cells in breast cancer cells.
- rhDCN's normalization effects were persistent across cell passages and in tumor xenografts.

## Abstract

What are the main findings?
rhDCN can normalize the active features of breast cancer-associated fibroblasts.rhDCN-dependent normalization of CAFs is persistent.

rhDCN can normalize the active features of breast cancer-associated fibroblasts.

rhDCN-dependent normalization of CAFs is persistent.

What are the implications of the main findings?
Utilization of rhDCN to target active CAFs in breast tumors.rhDCN could be used for the treatment of various types of cancer through the inhibition of the pro-carcinogenic effects of CAFs.

Utilization of rhDCN to target active CAFs in breast tumors.

rhDCN could be used for the treatment of various types of cancer through the inhibition of the pro-carcinogenic effects of CAFs.

Cancer-associated fibroblasts (CAFs), the major constituent of the tumor microenvironment, are considered the most active cells and key contributors to tumor resistance, recurrence, and metastasis. Therefore, we have investigated here the potential normalization of the active features of breast CAFs with decorin (DCN), a small leucine-rich proteoglycan that acts as an oncogene suppressor. We have first shown that rhDCN modulates the expression of a plethora of proteins involved in different signaling pathways, including STAT3/NF-κB and ERK. Consequently, rhDCN repressed the important active CAF biomarkers α-SMA, IL-6, and SDF-1 through inhibition of the STAT3/AUF-1 pathway, in cells grown as 2D and 3D cultures. Furthermore, rhDCN had a strong downregulation effect on FAP-α, a key biomarker of active CAFs, and suppressed their proliferative and invasive capacities through upregulation of p16 and p21, and downregulation of MMP-2 and MMP-9. Furthermore, rhDCN suppressed the paracrine effects of active CAFs in promoting epithelial-to-mesenchymal transition (EMT) and cancer stem cells in breast cancer cells, both in vitro and in orthotopic tumor xenografts. Importantly, rhDCN-related normalization of active CAFs features was persistent through cellular passaging, and was not accompanied by cytotoxicity. Together, these findings have revealed rhDCN as a promising anti-breast cancer therapeutic cytokine through suppression of the non-cell-autonomous cancer-promoting effects of active CAFs.