Estrogen-induced SDF-1α production promotes the progression of ER-negative breast cancer via the accumulation of MDSCs in the tumor microenvironment.

Liquan Ouyang,Weilong Chang,Bin Fang,Jieting Qin,Xincai Qu,Fanjun Cheng

doi:10.1038/srep39541

Abstract

Estrogen plays a role in the processes of tumorigenesis, metastasis, and drug resistance in estrogen receptor (ER)-positive breast cancer (BC). Whether estrogen contributes to ER-negative BC is unclear. Here, we aimed to investigate whether estrogen could stimulate the secretion of stromal-derived factor-1 (SDF-1α) by cancer-associated fibroblasts (CAFs) to promote the progression of ER-negative BC. We transplanted ER-negative BC cells into ovariectomized mice, which was followed by continuous injection of estrogen, and found that estrogen promoted the tumorigenesis of BC. Furthermore, High levels of SDF-1α and tumor-infiltrating myeloid-derived suppressor cells (MDSCs) were detected in the estrogen treatment group. Estrogen stimulates secretion of SDF-1α by CAFs extracted from BC patients. Recombinant SDF-1α could recruit MDSCs isolated from bone marrow cells of mice. In addition, the co-culture of CAFs and MDSCs demonstrated that the recruitment of MDSCs was increased when CAFs were exposed to estrogen. Using AMD3100 to block the SDF-1α/CXCR4 axis or gemcitabine to delete MDSCs, we observed that both of these agents could neutralize the effect of estrogen on tumorigenesis. Together, these results suggest that estrogen may promote the progression of ER-negative BC by stimulating CAFs to secrete SDF-1α, which can recruit MDSCs to the tumor microenvironment to exert tumor-promoting effects.

Highlights

Lewis lung carcinoma cells and the tumorigenesis of PC-3 human prostate cancer cells, which lack ERα/βexpression
The role that estrogen plays in estrogen receptor (ER)-positive Breast cancer (BC) is well-documented, but the manner in which it contributes to ER-negative breast cancer, which is a more aggressive disease, remains unclear
The results showed that the tumor sizes in the estrogen group were larger than those in the control group, which indicated that estrogen increased the tumorigenic ability of ER-negative BC cells (Fig. 1)

Summary

Introduction

Lewis lung carcinoma cells and the tumorigenesis of PC-3 human prostate cancer cells, which lack ERα/βexpression. Cancer-associated fibroblasts (CAFs), which are known as active stromal cells, play important roles in influencing tumor progression. SDF-1αis produced by stromal and tumor cells in the tumor microenvironment It exerts multiple tumor-promoting functions via either its receptor CXCR4, which is expressed on cancer cells and enhances tumor growth and metastasis, or the recruitment of endothelial progenitors for tumor angiogenesis. It is possible that CAFs within breast tumors exert tumor-promoting effects largely through the secretion of SDF-1α, which acts through the cognate receptor CXCR4 on cancer cells and the recruitment of MDSCs for immune escape. We found that estrogen stimulated CAFs to produce SDF-1α, which recruits MDSCs into the tumor microenvironment, where they exert tumor-promoting effects. Inhibition of the recruitment of MDSCs can reverse the tumor-promoting effects of estrogen in ER-negative BC

Objectives

Methods

Results

Conclusion