Stromal Fibroblasts from the Interface Zone of Triple Negative Breast Carcinomas Induced Epithelial-Mesenchymal Transition and its Inhibition by Emodin.

Hsiang-Chi Hsu,Chi-Tang Ho,Ying-Chao Lin,Chao-Ming Hung,Tzong-Der Way,Liang-Chih Liu,Hao-Yu Wang,Ying-Jan Wang

doi:10.1371/journal.pone.0164661

Abstract

“Triple negative breast cancer” (TNBC) is associated with a higher rate and earlier time of recurrence and worse prognosis after recurrence. In this study, we aimed to examine the crosstalk between fibroblasts and TNBC cells. The fibroblasts were isolated from TNBC patients’ tissue in tumor burden zones, distal normal zones and interface zones. The fibroblasts were indicated as cancer-associated fibroblasts (CAFs), normal zone fibroblasts (NFs) and interface zone fibroblasts (INFs). Our study found that INFs grew significantly faster than NFs and CAFs in vitro. The epithelial BT20 cells cultured with the conditioned medium of INFs (INFs-CM) and CAFs (CAFs-CM) showed more spindle-like shape and cell scattering than cultured with the conditioned medium of NFs (NFs-CM). These results indicated that factors secreted by INFs-CM or CAFs-CM could induce the epithelial-mesenchymal transition (EMT) phenotype in BT20 cells. Using an in vitro co-culture model, INFs or CAFs induced EMT and promoted cancer cell migration in BT20 cells. Interestingly, we found that emodin inhibited INFs-CM or CAFs-CM-induced EMT programming and phenotype in BT20 cells. Previous studies reported that CAFs and INFs-secreted TGF-β promoted human breast cancer cell proliferation, here; our results indicated that TGF-β initiated EMT in BT20 cells. Pretreatment with emodin significantly suppressed the TGF-β-induced EMT and cell migration in BT20 cells. These results suggest that emodin may be used as a novel agent for the treatment of TNBC.

Highlights

Breast cancer is the most commonly diagnosed cancer in women and affects the lives of millions of women worldwide each year
We demonstrated the differential interactions between fibroblasts from different tumor zones and triple-negative breast cancer (TNBC) cells
Our study found that cancer-associated fibroblasts (CAFs) and interface zone fibroblasts (INFs) grown with human TNBC BT20 cells dramatically promoted cell migration and induced an epithelial-mesenchymal transition (EMT) process

Summary

Introduction

Breast cancer is the most commonly diagnosed cancer in women and affects the lives of millions of women worldwide each year. The specific group accounts for approximately 15–20% of all breast cancer is triple-negative breast cancer (TNBC). TNBC is defined by the lack of demonstrable expression of the estrogen receptor (ER), progesterone receptor (PR) or HER2 proteins [1]. TNBC has a higher rate of distant recurrence and shorter overall survival in the metastatic setting compared with other subtypes of breast cancer. Metastatic TNBC is an aggressive disease and the median survival is less than one year. Almost all TNBC patients die from the progression of their disease despite adjuvant chemotherapy [2]. Novel anti-cancer drugs with higher efficiency and specificity are urgently needed

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